Getting Personal: Omics Of The Heart podcast

#Science #Cardiovasculardisease #Precisionmedicine #Biology #Medicine #Fitness #American Heart Association #Jane Ferguson #Genomics

23:28

My guest today has been keeping us up to date with the current state of hiring for marketers on a quarterly basis, which has taken us on quite a roller coaster ride. Today we’re going to look at how marketing and communication execs are responding to the latest developments in the world while still needing to get their work done. To take a look at the latest here, I’d like to welcome back to the show Sue Keith, Corporate Vice President at Landrum Talent Solutions. About Sue Keith Sue Keith is Corporate Vice President at Landrum Talent Solutions. With deep expertise in navigating complex labor markets, Sue has a front-row seat to the evolving dynamics of marketing roles, hiring trends, and the broader implications of AI and economic uncertainty. RESOURCES Landrum Talent Solutions: https://www.landrumtalentsolutions.com https://www.landrumtalentsolutions.com This episode is brought to you by Landrum Talent Solutions, a national recruiting firm specializing in marketing and HR positions. https://www.landrumtalentsolutions.com Catch the future of e-commerce at eTail Boston, August 11-14, 2025. Register now: https://bit.ly/etailboston and use code PARTNER20 for 20% off for retailers and brands Online Scrum Master Summit is happening June 17-19. This 3-day virtual event is open for registration. Visit www.osms25.com and get a 25% discount off Premium All-Access Passes with the code osms25agilebrand Don't Miss MAICON 2025, October 14-16 in Cleveland - the event bringing together the brights minds and leading voices in AI. Use Code AGILE150 for $150 off registration. Go here to register: https://bit.ly/agile150 Connect with Greg on LinkedIn: https://www.linkedin.com/in/gregkihlstrom Don't miss a thing: get the latest episodes, sign up for our newsletter and more: https://www.theagilebrand.show Check out The Agile Brand Guide website with articles, insights, and Martechipedia, the wiki for marketing technology: https://www.agilebrandguide.com The Agile Brand is produced by Missing Link—a Latina-owned strategy-driven, creatively fueled production co-op. From ideation to creation, they craft human connections through intelligent, engaging and informative content. https://www.missinglink.company…

Getting Personal: Omics of the Heart

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Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.

37 епізодів

Getting Personal: Omics of the Heart

updated 5 років тому

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Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.

37 епізодів

#Science #Cardiovasculardisease #Precisionmedicine #Biology #Medicine #Fitness #American Heart Association #Jane Ferguson #Genomics

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Getting Personal: Omics of the Heart

1
February 2020 13:05

5 years тому13:05

13:05

Jane Ferguson: Hi there. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson, and this is Episode 36 from February 2020. First up, we have “Identification of Circulating Proteins Associated with Blood Pressure Using Mendelian Randomization” from Sébastien Thériault, Guillaume Paré, and colleagues from McMaster University in Ontario. They set out to assess whether they could identify protein biomarkers of hypertension using a Mendelian randomization approach. They analyzed data from a genome-wide association study of 227 biomarkers which were profiled on a custom Luminex-based platform in over 4,000 diabetic or prediabetic participants of the origin trial. They constructed genetic predictors of each protein and then used these as instruments for Mendelian randomization. They obtained systolic and diastolic blood pressure measurements in almost 70,000 individuals, in addition to mean arterial pressure and pulse pressure in over 74,000 individuals, all European ancestry with GWAS data, as part of the International Consortium for Blood Pressure. Out of the 227 biomarkers tested, six of them were significantly associated with blood pressure traits by Mendelian randomization after correction for multiple testing. These included known biomarkers such as NT-proBNP, but also novel associations including urokinase-type plasminogen activator, adrenomedullin, interleukin-16, cellular fibronectin and insulin-like growth factor binding protein-3. They validated all of the associations apart from IL-16 in over 300,000 participants in UK Biobank. They probed associations with other cardiovascular risk markers and found that NT-proBNP associated with large artery atherosclerotic stroke, IGFBP3 associated with diabetes, and CFN associated with body mass index. This study identified novel biomarkers of blood pressure, which may be causal in hypertension. Further study of the underlying mechanisms is required to understand whether these could be useful therapeutic targets in hypertensive disease. The next paper comes from Sony Tuteja, Dan Rader, Jay Giri and colleagues from the University of Pennsylvania and it's entitled, “Prospective CYP2C19 Genotyping to Guide Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Pragmatic Randomized Clinical Trial”. They designed a pharmacode genomic trial to assess effects of CYP2C19 genotyping on antiplatelet therapy following PCI. Because loss of function alleles in CYP2C19 impair the effectiveness of clopidogrel, the team were interested in understanding whether knowledge of genotype status would affect prescribing in a clinical setting. They randomized 504 participants to genotype guided or usual care groups and assessed the rate of prasugrel or ticagrelor prescribing in place of clopidogrel within each arm. As a secondary outcome, they assessed whether prescribers adhere to genotype guided recommendations. Of genotyped individuals, 28% carried loss of function alleles. Within the genotype guided group overall, there was higher use of prasugrel or ticagrelor with these being prescribed to 30% of patients compared with only 21% in the usual care group. Within genotype individuals carrying loss of function alleles, 53% were started on prasugrel or ticagrelor, demonstrating some adherence to genotype guided recommendations. However, this also meant that 47% of people whose genotype suggested reduced effectiveness were nevertheless prescribed clopidogrel. This study highlights that even when genotype information is available, interventional cardiologists consider clinical factors such as disease presentation and may weight these more highly than genotype information when selecting antiplatelet therapy following PCI. The next paper is about “Deep Mutational Scan of an SCN5A Voltage Sensor and comes to us from Andrew Glazer, Dan Roden and colleagues from Vanderbilt University Medical Center. In this paper, the team aim to characterize the functional consequences of variants and the S4 voltage sensor of domain IV and the SCN5A gene using a high throughput method that they developed. SCN5A encodes the major voltage gated sodium channel in the heart and variants in SCN5A can cause multiple distinct genetic arrhythmia syndromes, including Brugada syndrome, long QT syndrome, atrial fibrillation, and dilated cardiomyopathy, and have been linked to sudden cardiac death. Because of this, there's considerable interest in understanding the functional and clinical consequences of different variants, but previous approaches were time consuming and results were often inconclusive with many variants being classified as uncertain significance. This newly developed deep mutational scanning approach allows for simultaneous assessment of the function of thousands of variants, making it much more efficient than low throughput patch clamping. The team assessed the function of 248 variants using a triple drug assay in HEK293T cells expressing each variant and they identified 40 putative gain of function and 33 putative loss of function variants. They successfully validated eight of nine of these by patch clamping data. Their study highlights the effectiveness of this deep mutational scanning approach for investigating variants in the cardiac sodium channel SCN5A gene and suggests that this may also be an effective approach for investigating putative disease variants and other ion channels. The next article is a research letter from Connor Emdin, Amit Khera, and colleagues from Mass General Hospital in the Broad Institute entitled, “Genome-Wide Polygenic Score and Cardiovascular Outcomes with Evacetrapib in Patients with High-Risk Vascular Disease: A Nested Case-Control Study”. In this study, the team set out to probe the utility of using polygenic risk scores to predict the risk of major adverse cardiovascular events within individuals already known to be at high cardiovascular risk and to assess whether genetic scores can identify individuals who would benefit from the use of a CETP inhibitor such as Evacetrapib. They analyze data from the ACCELERATE trial which had tested Evacetrapib in a high risk population, and they found no effect on the incidents of major adverse cardiovascular events overall. Within a nested case-control sample of individuals experiencing major CVD events versus no events, they applied a polygenic risk score and found that the score predicted major cardiovascular events. Patients in the highest quintile of the risk score were at 60% higher risk of a major cardiovascular event than patients in the lowest quintile. There was no evidence of any interaction between the genetic risk score and Evacetrapib. These data suggest that genetic risk scores may have utility in identifying individuals at high risk events but may not have utility in identifying individuals who may derive more benefit from CETP inhibition. The next letter concerns “Epigenome-Wide Association Study Identifies a Novel DNA Methylation in Patients with Severe Aortic Valve Stenosis” and comes from Takahito Nasu, Mamoru Satoh, Makoto Sasaki and colleagues from Iwate Medical University in Japan. They were interested in understanding whether differences in DNA methylation could underlie the risk of aortic valve stenosis. They conducted an EWAS or epigenome-wide association study of peripheral blood mononuclear cells or PBMCs from 44 individuals with aortic stenosis and 44 disease free controls. They collected samples at baseline before a surgical intervention in the individuals with aortic stenosis and collected a follow-up sample one year later. They found that DNA methylation at a site on chromosome eight mapping to the TRIB1, or tribbles homolog one gene, was lower in the aortic stenosis group than in the controls at baseline. They replicated the association in an independent sample of 50 cases and 50 controls. TRIB1 MRNA levels were higher in the aortic stenosis group than the controls. When they looked at methylation status one year after aortic valve replacement or a transcatheter aortic valve implantation in patients with stenosis, they found that DNA methylation had increased in the cases while TRIB1 MRNA decreased. These data suggests that methylation status of TRIB1 and expression of TRIB1 may relate to the disease processes in aortic stenosis such as hemodynamic dysregulation and they can be reversed through surgical intervention. Changes in the methylation status of TRIB1 could be a novel biomarker of response to aortic valve replacement. The next letter comes from Niels Grote Beverborg, Pim van der Harst, and colleagues from University Medical Center Groningen and is entitled, “Genetically Determined High Levels of Iron Parameters Are Protective for Coronary Artery Disease”. Their study addresses the conflicting hypotheses that high iron status is either deleterious or protective against cardiovascular disease. The team constructed genetic predictors of serum iron status using 11 previously identified snips and tested the genetic association with CAD in UK Biobank data from over 408,000 white participants. Overall, the genetic score for higher iron status was associated with protection against CAD. Ten of the snips suggested individual neutral or protective effects of higher iron status on CAD, while one iron increasing snip was associated with increased risk of disease but this was thought to be likely through an iron independent mechanism. Overall, these data suggest that a genetic predisposition to higher iron status does not increase risk of CAD and is actually protective against disease. The final letter is entitled, “Confidence Weighting for Robust Automated Measurements of Popliteal Vessel Wall MRI” and comes from Daniel Hippe, Jenq-Neng Hwang, and colleagues from the University of Washington. They were interested in assessing whether images of popliteal artery wall incidentally obtained during knee MRI as part of an osteoarthritis study could be used to study the development and progression of atherosclerosis. They developed an automated deep learning based algorithm to segment and quantify the popliteal artery wall in images obtained over 10 years in over 4,700 individuals. Their approach, which they named FRAPPE, or fully automated and robust analysis technique for popliteal artery evaluation, was able to reduce the average time required for segmentation analysis from four hours to eight minutes per image. They applied weights based on confidence for each segment to automatically improve the accuracy of aggregate measurements such as mean wall thickness or mean lumen area. Their data suggest that this automated method can rapidly generate useful information on atherosclerosis from MRI images obtained as part of other studies. When combined with other data. This approach may facilitate novel discovery in secondary analyses of existing studies in an efficient and cost effective way. And that's all for issue one of 2020. Come back next time for more of the latest papers from Circulation: Genomic and Precision Medicine. Speaker 2: This podcast is copyright American Heart Association 2020.…

Getting Personal: Omics of the Heart

1
December 2019 10:35

5 years тому10:35

10:35

Jane Ferguson: Hi, everyone. Welcome to episode 35 of Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson, an assistant professor of medicine at Vanderbilt University Medical Center, and an associate editor at Circulation: Genomic and Precision Medicine . This episode is first airing in December 2019. Let's see what we published this month. Our first paper is an “Integrated Multiomics Approach to Identify Genetic Underpinnings of Heart Failure and Its Echocardiographic Precursors: The Framingham Heart Study” from Charlotte Anderson, Ramachandran Vasan and colleagues from Herlev and Gentofte Hospital, Denmark and Boston University. In this paper, the team investigated the genomics of heart failure, combining GWAS with methylation and gene expression data, to prioritize candidate genes. They analyzed four heart failure related and eight echocardiography related phenotypes in several thousand individuals, and then identified SNPs, methylation markers, and differential gene expression associated with those phenotypes. They then created scores for each gene, based on the rank of statistical significance, aggregated across the different omics analysis. They examined the top ranked genes for evidence of pathway enrichment, and also looked up top SNPs for PheWAS associations in UK Biobank, and examined tissue specific expression in public data. While their data cannot definitively identify causal genes, they highlight several genes of potential relevance to heart failure pathogenesis, which may be promising candidates for future mechanistic studies. The next paper is “Genetic Determinants of Lipids and Cardiovascular Disease Outcomes: A Wide-Angled Mendelian Randomization Investigation” and comes from Elias Allara, Stephen Burgess and colleagues, from the University of Cambridge and the INVENT consortium. While it has been established, therapies to lower LDL cholesterol and triglycerides lead to lower risk of coronary artery disease, it remains less clear whether these lipid lowering efforts can also reduce risk for other cardiovascular outcomes. The team set out to address this question using Mendelian randomization. They generated genetic predictors of LDL cholesterol and triglycerides using data from the Global Lipids Genetics Consortium, and then assessed whether genetically predicted increased LDL and triglycerides associated with risk of cardiovascular phenotypes using UK Biobank data. Beyond CAD, they found that higher LDL was associated with abdominal aortic aneurysm and aortic valve stenosis. High triglyceride levels were positively associated with aortic valve stenosis and hypertension, but inversely associated with venous thromboembolism and hemorrhagic stroke. High LDL cholesterol and triglycerides were also associated with heart failure, which appeared to be mediated by CAD. Their data suggests that LDL lowering may have additional cardiovascular benefits in reducing aortic aneurism and aortic stenosis, while efforts to lower triglycerides may reduce the risk of aortic valve stenosis, but could result in increased thromboembolic risk. Next up is a paper from Steven Joffe, G.L. Splansky and colleagues, from the University of Pennsylvania and Boston University, on “Preferences for Return of Genetic Results Among Participants in the Jackson Heart Study and Framingham Heart Study”. There has been increasing discussion and concern about how to handle genetic data, and whether genetic results should be returned to participants, and under which circumstances. In this study, the teams that had to assess what participants themselves think. They query participants in the Jackson Heart Study, the Framingham Heart Study and the FHS Omni cohort, presenting them with potential scenarios that varied by five factors including phenotype severity, actionability, reproductive significance and relative of the absolute risk of the phenotype. Across all scenarios, 88 to 92% of respondents said that they would definitely or probably want to learn their result. In Jackson Heart Study respondents, factors increasing the desire for results included a positive attitude towards genetic testing, lower education, higher subjective numeracy, and younger age. The five pre-identified factors did not affect desire to receive results in Jackson Heart Study. Among Framingham Heart Study respondents, desire for results was associated with higher absolute risk, presentability, reproductive risk and positive attitudes towards genetic testing. Among FHS Omni respondents, desire for results was associated with positive attitudes towards genetic testing and younger age. Overall, these data show that across a variety of studies, there a high level of interest in receiving genetic results and that these are not necessarily linked to the phenotype or clinical significance of the results themselves. The next paper concerns “Peripheral Blood RNA Levels of QSOX1 and PLBD1 Are New Independent Predictors of Left Ventricular Dysfunction after Acute Myocardial Infarction” and this comes from Martin Vanhaverbeke, Peter Sinnaeve and colleagues, from University Hospital Leuven. They were interested in understanding whether they could identify subsequent left ventricular dysfunction in patients who suffered an acute myocardial infarction. They obtained blood and performed RNA-Seq at multiple time points in 143 individuals, following acute MI, to identify transcripts that were associated with subsequent LV dysfunction. They validated candidate gene transcripts in a validation sample of 449 individuals, confirming that expression of QSOX1 and PLBD1 at admission, were associated with LV dysfunction at follow-up. Adding QSOX1 to a model, consisting of clinical variables and cardiac biomarkers, including NT proBNP, had an incremental predictive value. They took their findings to a pig model and found that whole blood expression of both genes was associated with neutrophil infiltration in these ischemic myocardium. This study suggests that expression of QSOX1 and PLBD1 following MI, may have utility in predicting development of LV dysfunction and may be markers of cardiac inflammation. The next paper is a research letter from Hanna Hanania, Denver Sallee and Dianna Milewicz, from the University of Texas Health Science Center, and Emory University School of Medicine. Who set out to answer the question, “Do HCN4 Variants Predisposed to Thoracic Aortic Aneurysms and Dissections?” Previous work has suggested that rare variants in HCN4 associated with thoracic aortic disease, including ascending aortic dilation, left ventricular noncompaction cardiomyopathy, and sinus bradycardia. However, the evidence for disease segregation was relatively weak. The team set out to explore these potential associations using exome sequencing data from 521 individuals, from 347 unrelated families with heritable thoracic aortic disease, as well as 355 individuals with early onset sporadic aortic dissections, but no family history of disease. They identified a missense variant G482R, which segregated with disease in four unrelated families, was absent from the nomad database and was predicted to disrupt protein function and have deleterious effects. Their data support the evidence that HCN4 rare variants can cause heritable thoracic aortic disease with left ventricular noncompaction cardiomyopathy and bradycardia. Our final paper is a white paper from H. Li, X. J. Luo and colleagues, from the National Heart, Lung and Blood Institute at the NIH, and will likely interest anybody who applies for NIH grants, which I'm assuming is most of you listening to this podcast. Their paper on, “Portfolio Analysis of Research Grants in Data Science Funded by the National Heart, Lung, and Blood Institute”, delves into the type of data science research funded by NHLBI between fiscal year 2008 and fiscal year 2017. They identified 630 data science focused grants, funded by NHLBI, using keywords for bioinformatics and computational biology. They then analyzed the distribution of these grants across different disease areas and compared the results to data science grants funded by other NIH institutes or centers. Around 64% of funded grants were for cardiovascular disease with 22% in lung and airway disease, 12% in blood disease and 2% in sleep. NHLBI's investment in data science research grants averaged about 1% of its overall research grant investment, and this remained constant over the 10-year period. However, this proportion does not include other large scale investment by NHLBI in building data science platforms through other mechanisms. Of relevance to our listeners across all institutes, most funded data science research grants were related to genomics and other omics data. In this paper they include lots of graphs breaking down grant distributions across different categories, so it's worth a look as you plan your next grant application. That's all for December and the final episode of 2019. Thanks for listening and happy holidays to all who celebrate. I'm excited to be back in 2020, to kick off the next decade of exciting advances in genomic and precision cardiovascular medicine. This podcast was brought to you by Circulation: Genomic and Precision Medicine , and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

1
34 November 2019 12:31

6 years тому12:31

12:31

Jane Ferguson: Hi there. Welcome to the November 2019 issue of Getting Personal: Omics of the Heart. I'm Jane Ferguson. This is your podcast from Circulation: Genomic and Precision Medicine . Let's get started. First up from Eric Curruth, Christopher Haggerty and colleagues from Geisinger, we have a paper entitled, “Prevalence and Electronic Health Record-based Phenotype of Loss-of-function Genetic Variance in Arrhythmogenic Right Ventricular Cardiomyopathy-associated Genes”. In this study, the team set out to understand the phenotypic consequences of variants and desmosome genes which has been associated with a arrhythmogenic right ventricular cardiomyopathy or ARVC. In clinical genetic testing, secondary findings of pathogenic or likely pathogenic variants in desmosome genes are recommended for clinical reporting. However, relatively little is known about the phenotypic consequences of these variants in a general clinical population. The team obtained whole exome sequencing data for over 61,000 individuals from the DiscovEHR cohort, part of the Geisinger MyCode Community Health Initiative. They then screened individuals for a putative loss of function variants in PKP2 , DSC2 , DSG2 , and DSP . They evaluated ARVC diagnostic criteria using previously conducted ECG and echocardiograms and performed a phenom-wide association study or PHeWAS using EHR derived phenotypes. They found 140 people with an ARVC variant in one of the four genes, none of whom had an existing diagnosis of ARVC in the EHR. Further, there were no measurable differences in their ECG or echocardiogram findings compared with matched controls. There were also no associations with any heart disease phenotypes as assessed by PHeWAS. Overall, they report a prevalence of ARVC loss of function variants of around one in 435 in a general clinical population of predominantly European descent, but they did not find evidence that these variants associated with specific phenotypes. Thus, the clinical relevance of putative loss of function variants in desmosome genes still remains to be determined. The next paper is titled, “ MRAS Variants Cause Cardiomyocyte Hypertrophy in Patients-specific iPSC-derived Cardiomyocytes”. Additional evidence for MRS as a definitive Noonan syndrome susceptibility gene. This comes from Erin Higgins, Michael Ackerman, and colleagues from the Mayo Clinic. They were interested in understanding whether a recently identified Noonan syndrome variant in the MRS gene was necessary and sufficient to cause Noonan syndrome with cardiac hypertrophy. They generated induced pluripotent STEM cell or IPS C lines from patient derived cells carrying the glycine 23 veiling variant and MRS. In addition to isogenic control cells where the pathogenic variant was corrected back to wild-type using CRISPR CAS nine gene editing, they also created a disease model cell line by introducing the MRS variant into unrelated control cells. They then comprehensively characterized the phenotypes of the three cell lines using a variety of approaches including microscopy, immunofluorescence, single cell RNA seek, Western blot, qPCR, and live cell calcium imaging. Both the patient derived and the disease model IPS cardiomyocytes were larger than control cells and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy. The patient and disease model cells also displayed impaired calcium handling. Through in-vitro phenotyping, the team was able to demonstrate that the glycine 23 veiling MRS variant elicits a cardiac hypertrophy phenotype and IPSC cardiomyocytes, that strongly suggests that this variant is responsible for the observed Noonan syndrome associated cardiac hypertrophy in the effected patients. Next up is a review from Christopher Lee, Iftikhar Kullo, and colleagues also from the Mayo Clinic on “New Case Detection by Cascade Testing in Familial Hypercholesterolemia: A Systematic Review of the Literature”. In this review they set out to systematically assess cascade testing programs for familial hypercholesterolemia, a disease which has a prevalence of about one and 250 but is estimated to be diagnosed in under 10% of patients. They identified published studies across the world which had conducted cascade testing and had reported the number of index cases and number of relatives tested and had also specified their methods of contacting relatives and testing. Using these criteria, they identified 10 studies for inclusion spanning several European countries, South Africa, New Zealand, Australia, and Brazil. The team calculated the proportion of relatives testing positive and the number of new cases per index case to facilitate comparison between studies. The mean number of programs was 242 with an average of 826 relatives per study. The average yield was 45%, ranging from 30 to 60%. the mean new cases per index case was 1.65 with a range of 0.22 to 8.0. Studies that use direct contact versus indirect contact for relatives and those that tested beyond first degree relatives had a greater yield. Further, active sample collection versus collection at clinic and using genetic testing versus biochemical testing was similarly associated with a higher yield. Despite differences between the United States and other countries, applying these strategies when establishing new cascade testing programs in the US may help promote success of these programs. Our next paper concerns “Randomization of Left-right Asymmetry and Congenital Heart Defects: The Role of DNAH5 in Humans and Mice”. And this was conducted by Tabea Nöthe-Menchen, Heymut Omran, and colleagues from University Children's Hospital Muenster and the PCD study group. They were interested in understanding the relationship between congenital heart defects and laterality defects where internal organs are atypically positioned, such as in a mirror image as occurs in situs inversus. Ciliary dyskinesia is thought to play a role in situs inversus and the most frequently mutated gene in primary ciliary dyskinesia is DNAH5 . The team does hypothesize that DNAH5 mutations may play a role in congenital heart disease. They characterized phenotypes in 132 patients with primary ciliary dyskinesia carrying disease causing DNAH5 mutations and also studied left right access establishment using a DNAH5 mutant mouse model. 66% of patients in their study had laterality defects, 88% of whom presented with situs inversus totalis and 6% presented with congenital heart disease. In the mass model, they observed immotile cilia, impaired flow with the left right organizer and randomization of nodal signaling with normal reversed or bilateral expression of key molecules. Their study thus demonstrates that mutation of DNAH5 is associated with congenital heart defects and they further highlight the ciliary mechanisms underlying defects and development of left right positioning during embryogenesis. Consideration of celiopathy related symptoms may be warranted when examining patients with congenital heart defects. Next up, we have a research letter from William Goodyear, Marco Perez and colleagues from Stanford University on “Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titan Loss-of-Function Variants in Very Early-Onset Atrial Fibrillation”. They were interested in understanding genetic determinants of atrial fibrillation and hypothesized that causal genetic variants would be enriched in individuals with very early onset AF, who are diagnosed with AF under the age of 45 with no other significant comorbidities. They identified 25 families comprising 23 unrelated patients with very early onset AF who had been evaluated and received genetic counseling at Stanford between 2014 and 2018. The mean age of AF diagnosis was 27.2 years and 76% of patients were male. 40% of patients had a first or second degree relative with very early onset AF, while 36% at first or second degree relatives with either early onset idiopathic cardiomyopathy, unexplained sudden death or strokes. 85% of patients were identified as having at least one rare variant in a cardiomyopathy associated gene. Six patients carried actionable pathogenic or likely pathogenic variants, four of which were in the titan gene. A subset of individuals were further evaluated by MRI or computed tomography on average 817 days after their first presentation and this revealed high rates of cardiac abnormalities including reduced ventricular function, chamber enlargement, borderline LV non compaction, or late gadolinium enhancement. These were not noted on echocardiogram at presentation, suggesting there may have been subsequent disease development or progression. Overall, this study highlights a high rate of familial disease and implicates an association between very early onset AF and rare variants in titan before the clinical onset of cardiomyopathy. The final letter this month comes from Yu Xia, Shaoxian Chen, Ping Li, Jian Zhuang and colleagues from Guangdong Academy of Medical Sciences and is entitled, “A Novel Mutation in MYH6 in Two Unrelated Chinese Han Families with Familial Atrial Septal Defect”. They report on two unrelated families who presented with secundum atrial septal defect or ASD2. Whole exome sequencing revealed a novel variant and the MYH6 gene in both families, with the same variant present in all effected individuals but not in unaffected family members or unrelated controls. Because other variants in MYH6 have been reported to effect myofibril formation. The team studied the effect of the novel variant on the myofibrillar organization through transient transfection of CTC 12 cells. The MYH6 E526K variant was associated with a reduced striated I pattern and increased non-striated patterning. There was no effect on ATPase activity. Protein modeling suggested a variant of the effective position would reduce hydrogen bonding between alpha helices in the actin interface two region, increasing the volume of the cavity between the alpha helices and promoting the exposure of the alkaline side chain in the actin binding region. This could impair the interaction between the myosin motor head and actin. What these data suggests are that this novel MYH6 heterozygous variant may underlie ASD2 in two unrelated Chinese Han families by impairing myofibrillar organization. That's all for November 2019. Thank you for listening and I look forward to being back in December for the final episode of 2019. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association council on genomic and precision medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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33 October 2019 9:10

6 years тому9:10

9:10

Jane Ferguson: Hello. Welcome to episode 33 of Getting Personal: Omics Of The Heart, your podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson. This episode is from October 2019. Let's get started. First up is a paper from Sébastien Thériault, Yohan Bossé, Jean-Jacques Schott and colleagues from Laval University, Quebec and INSERM in Mont. They published on genetic association analyses, highlight IL6, ALPL and NAV1 as three new susceptibility genes underlying Calcific Aortic Valve Stenosis. In this paper, they were interested in finding out whether they could identify novel susceptibility genes for Calcific Aortic Valve Stenosis, or CAVS, which is a severe and often fatal condition with limited treatment options other than surgical aortic valve replacement. They conducted a GWAS meta-analysis across four European ancestry cohorts comprising over 5,000 cases and over 354,000 controls. They identified four loci at genome-wide significance, including two known loci in LPA and PALMD as well as two novel loci, IL6 which encodes the interleukin six cytokine, and ALPL, which encodes an alkaline phosphatase. They then integrated transcriptomic data from 233 human aortic valves to conduct the transcriptome wide association study and find an additional risk locus associated with higher expression of NAV1 encoding neuron navigator one. Through fine mapping, integrating conservation scores, and methylation peaks, they narrowed down the putative causal variants at each locus identifying one snip in each of PALMD and IL6 as likely causal in addition to two candidates snips at ALPL and three plausible candidate snips in NAV1. Phenome-Wide Association Analysis, or PheWAS of the top candidate functional snips found that the IL6 risk variant associated with higher eosinophil count, pulse pressure and systolic blood pressure. Overall, this study was able to identify novel loci associated with CAVS potentially implicating inflammation and hypertension in CAVS etiology. Additional functional studies are required to further explore these potential mechanisms. Next up is a paper from Elisavet Fotiou, Bernard Keavney and colleagues from the University of Manchester. Their paper entitled Integration of Large-Scale Genomic Data Sources With Evolutionary History Reveals Novel Genetic Loci for Congenital Heart Disease explored the genetic etiology of sporadic non syndromic congenital heart disease using an evolution informed approach. Ohnologs are related genes that have been retained following ancestral whole genome duplication events which occurred around 500 million years ago. The authors hypothesized that ohnologs which were retained versus duplicated genes that were lost were likely to have been under greater evolutionary pressure due to the need to maintain consistent gene dosage. For example, as could occur when the resulting proteins form complexes that require stochiometric balance. Thus, ohnologs may be enriched for genes that are sensitive to dosage. The group analyzed copy number variant data from over 4,600 non syndromic coronary heart disease patients as well as whole exome sequence data from 829 cases of Tetralogy of Fallot. Compared to control data obtained from public databases, there was evidence for significant enrichment in CHD associated variants in ohnologs but not in other duplicated genes arising from small scale duplications. Through this and various other filtering steps to prioritize likely variants, the group was able to identify 54 novel candidate genes for congenital CHD highlighting the utility of considering the evolutionary origin of genes in the search for disease relevant biology. Next, we have a clinical letter entitled Pathological Overlap of Arrhythmogenic Right Ventricular Cardiomyopathy and Cardiac Sarcoidosis from Ashwini Kerkar, Victoria Parikh and colleagues at Stanford University. They describe a case of a 50 year old woman previously healthy and a long distance runner who presented with tachycardia. She was found to have normal left ventricular size but severe right ventricular enlargement and systolic dysfunction. Genetic testing using an Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC panel identified a variant in DSG2. through cascade testing it was found that two of the patient's three children also carried this variant. The patient experienced worsening RV failure and subsequently underwent heart transplantation at age 55. Pathology of the heart showed evidence of cardiac sarcoidosis. There have been some previous reports of overlap in ARVC and cardiac sarcoid pathology but not in cases with a high confidence genetic diagnosis such as this one. This case raises the possibility of shared disease mechanisms underlying ARVC and cardiac sarcoidosis and suggests that therapies aimed at immune modulation may also have utility in ARVC. However, further work is required to test this hypothesis. Our next paper is a perspective piece from Babken Asatryan and Helga Servatius from Bern University Hospital. In Revisiting the Approach to Diagnosis of Arrhythmogenic Cardiomyopathy: Stick to the Arrhythmia Criterion!, they outline the challenges in defining diagnostic criteria for a Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC, given the variable presentation of the disease. Given recent advances in knowledge, particularly in recognizing disease overlap with Arrhythmogenic Left Ventricular Cardiomyopathy or ALVC and Biventricular Arrhythmogenic Cardiomyopathy, a new clinical perspective was warranted. The Heart Rhythm Society updated their recommendations this year to introduce a new umbrella term that better encompasses the spectrum of disease, Arrhythmogenic Cardiomyopathy or ACM. This recommends the arrhythmia criterion Should be used as a first line screening criteria for ACM. This is a broad criteria and a definitive diagnosis of ACM requires exclusion of systemic disorders such as sarcoidosis, amyloidosis, mild carditis, Chagas disease, and other cardiomyopathies. Implementation of this new approach to diagnosis may require more extensive investigation of arrhythmias including the use of ambulatory ECG monitors or cardiac loop recorders. These changes may also affect who's referred for genetic testing, potentially shifting diagnoses towards genotype rather than phenotype based disease classifications. Despite challenges and adopting new approaches, it is hoped that these changes will ultimately serve to improve risk stratification and allow for improved disease management and intervention to prevent sudden cardiac death. We end with a scientific statement chaired by Sharon Cresci and co-chaired by Naveen Pereira with a writing group representing the AHA Councils on Genomic and Precision Medicine, Cardiovascular and Stroke Nursing and Quality of Care and Outcomes Research entitled Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association. This paper provides a comprehensive overview of the current state of omics technologies as they relate to the development and progression of heart failure and considers the current and potential future applications of these high throughput data for precision medicine with respect to prevention, diagnosis and therapy of heart failure. They discuss advances in genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and the microbiome, and integrate the findings from this rapidly developing field as they pertain to new methods to diagnose, treat, and prevent heart failure. And that's it for October. I hope to see many of you at AHA Scientific Sessions in Philadelphia in November and look forward to bringing you more of the best new science next month. Thanks for listening. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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32 September 2019 10:33

6 years тому10:33

10:33

Jane Ferguson: Hi, everyone. Welcome to Getting Personal: Omics of the Heart, the monthly podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson, an assistant professor of medicine at Vanderbilt University Medical Center and an associate editor at CircGen. This is episode 32 from September 2019. Starting off this month, we have a paper on Genetic Mosaicism in Calmodulinopathy brought to us by Lisa Wren, Alfred George and colleagues from Northwestern University. They were interested in exploring the disease phenotypes that result from variation in the calmodulin genes, CALM1, 2 and 3. Mutations in calmodulin are known to associate with congenital arrhythmia, but the group hypothesized that there may be a broader range of phenotypes associated with calmodulin mutations. They report on four unrelated families all with pro bands exhibiting symptoms of prolonged QTC interval and documented ventricular arrhythmia. They conducted targeted exome sequencing in these individuals and in their families and identified mutations in calmodulin genes, including two novel mutations. In one family with multiple occurrences of intrauterine fetal demise, there was evidence for sematic mosaicism in both parents. The team studied the two novel mutations and found that the variants led to alterations in a calcium binding site resulting in impaired calcium binding. In human induced pluripotent stem cell derived cardiomyocytes, the team showed that the mutations impaired calcium dependent inactivation of L-type calcium channels and prolonged action potential duration. Their study not only demonstrates that mutations in calmodulins can cause dysregulation of L-type calcium channels, but that parental mosaicism maybe a factor in families with unexplained fetal arrhythmia or fetal demise. Our next paper come from Wan G Pang, Christiana Kartsonaki, Michael Holmes and Zing Min Chen from the University of Oxford and Peking University Health Science Center and is entitled Physical Activity, Sedentary Leisure Time, Circulating Metabolic Markers, and Risk of Major Vascular Diseases. In this study, the authors were interested in finding out whether circulating metabolites are associated with the relationship between physical inactivity or sedentary behavior and increased risk of cardiovascular disease. They identified over 3000 cases of incident CVD from the China Kadoorie Biobank and included over 1400 controls without CVD. They measured 225 different metabolites and baseline plasma samples using NMR. They used measures of self-reported physical activity and sedentary leisure time to associate physical activity with circulating metabolites, and then they ran analysis to relate the metabolites to CVD. Physical activity and sedentary leisure time were associated with over 100 metabolic markers. In general, the patterns of associations were similar using either activity measure. Physical activity was inversely related to very low and low density HDL particles, but positively related to large and very large HDL particle concentrations. Physical activity was also inversely associated with alanine, glucose, lactate, acetoacetate, and glycoprotein acetyls. When they examined the associations of these same metabolites with CVD, the directions were generally consistent with expectation, going on the premise that physical activity is protective, and that sedentary behavior is a risk factor for CVD. Their analyses suggests that metabolite markers could explain about 70% of the protective associations of physical activity and around 50% of the risk associations of sedentary leisure time with cardiovascular disease. Next up, we have a paper on Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy, coming from Judith Verhagen, Ingrid van de Laar and colleagues from University Medical Center Rotterdam. Their focus was on pediatric cardiomyopathies, which are both clinically and genetically heterogeneous. They had identified a family where two siblings had died during early infancy of rapidly progressive dilated cardiomyopathy. Through exome sequencing, they identified variants in the ASNA-1 gene and established that the children were compound heterozygotes for the variants. This highly conserved gene encodes an ATPase, which is required for post-translational membrane insertion of tail-anchored proteins. The team looked at expression of this protein in patient samples and then followed this up with functional analyses using cells and zebrafish. They found that one of the variants was predicted to result in a premature stop codon. In support of this, they observed decreased protein expression in myocardial tissue and skin fibroblasts. The other variant caused a missense mutation, and the team found that this resulted in protein misfolding, as well as less effective tail-anchored protein insertion. In zebrafish, knock out of the ASNA1 gene resulted in reduced cardiac contractility and early lethality, which could not be rescued by either version of the variant mRNA. This translational study highlights the importance of the ASNA1 gene as a cardiomyopathy susceptibility gene and further reveals the importance of tail-anchored membrane protein insertion pathways in cardiac function. The next paper from Karni Moshal, Gideon Koren and colleagues from Brown University is entitled LITAF Regulates Cardiac L-Type Calcium Channels by Modulating NEDD 4-1 Ubiquitin Ligase. In this paper, the authors report on the role of ubiquitination as a crucial component in cardiac ion channel turnover and action potential duration. Previous genome wide association studies of QT interval had identified snips in or near genes regulating protein ubiquitination, particularly the LITAF or lipopolysaccharide-induced tumor necrosis factor gene. Using zebrafish, the team performed optical mapping in hearts to identify calcium and found that knocked down of LITAF resulted in an increase in calcium transients. They studied intracellular calcium handling and rapid derived cardiomyocytes and found that over expression of LITAF caused a decrease in L-type calcium channel current and abundance of the L-type calcium channel alpha1c sub unit or Cava1c, whereas LITAF knocked down increased calcium channel current and Cava1c protein. LITAF downregulated total and surface pools of Cava1c via increased Cava1c ubiquitination and lysosomal degradation in tsA201 kidney cells. There was evidence of colocalization between LITAF and L-type calcium channel, or LTCC, in the tsA201 kidney cells and in cardiomyocytes. In the tsA201 cells, NEDD4-1 protein increased Cava1c ubiquitination, but a catalytically inactive form of NEDD4-1 had no effect. Cava1c ubiquitination was further increased by co-expressed LITAF NEDD4-1, but not the inactive version of NeNEDD4-1. NEDD4-1 knockdown abolished the negative effect of LITAF on L-type calcium channel current and Cava1c levels in three week old rapid cardiomyocytes. Taken together, these data show that LITAF acts as an adapter protein promoting NEDD4-1 mediated ubiquitination and subsequent degradation of LTCC, highlighting LITAF as a novel regulator of cardiac excitation. Rounding out this issue is a review on the Gut Microbiome and Response to Cardiovascular Drugs from Sony Tuteja and Jane Ferguson from the University of Pennsylvania and Vanderbilt University Medical Center. Since that last author is me, I'm sure I have a biased view of the importance of the topic, but the increasing awareness of the microbiome in every aspect of health has also led to increased awareness of the role of commensal microbiota in drug metabolism, including in the metabolism of drugs used to treat cardiovascular diseases. In this article, we aim to review what is currently known about how the gut microbiome interacts with cardiovascular drugs and to summarize some of the mechanisms whereby gut microbiota might affect drug metabolism. Early evidence suggests that the gut microbiome modulates response to statins and antihypertensive medications, but there may be many other drugs that are susceptible to interaction with microbiota. Drug metabolism by the gut microbiome can result in altered drug pharmacokinetics and pharmacodynamics or in the formation of toxic metabolites which can interfere with drug response. While we are still in a relatively early stage in this field, we suggest that a better understanding of the complex interactions of the gut microbiome, host factors and response to medications will be important for the development of novel precision therapeutics in cardiovascular disease prevention and treatment. That's all for the September issue of Circulation: Genomic and Precision Medicine . Come back next month for the next installment. Thanks for listening. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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27 August 2019 8:23

6 years тому8:23

8:23

Jane Ferguson: Hello, and welcome to Getting Personal, Omics of the Heart, your monthly podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson. It is August, 2019, and this is episode 31. Let's get started. Our first paper comes from Freyja van Lint and Cynthia James, from University Medical Center Utrecht, and is entitled Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo, Segregation and Haplotype Analysis of a Multinational Cohort. In this study, the team was interested in exploring variants that are associated with arrhythmogenic right ventricular cardiomyopathy or ARVC. ARVC is often attributable to pathogenic variants in genes encoding cardiac desmosomal proteins, but the origin of these variants had not been comprehensively studied. The investigators identified ARVC probands meeting 2010 task force criteria from three ARVC registries in the United States and Europe and who had undergone sequencing of desmosomal genes. All 501 probands, 322 of them, or over 64%, carried a pathogenic or likely pathogenic variant in the desmosomal genes PKP2, DSP DSG2, DSC2, and JUP. The majority of these, over 75%, we're not unique with these variants occurring in more than one proband. The team performed cascade screening and were able to identify the parental origin of almost all of the variants. However, they identified three de novo variants, including two whole gene deletions. They conducted haplotype analysis for 24 PKP2 variants across 183 seemingly unrelated families and concluded that all of these variants originated from common founders. This analysis sheds light on the origin of variants in desmosomal genes and suggests that the vast majority of these ARVC variants originate from ancient founders with only a very small proportion of de novo variants. These data can inform clinical care particularly concerning genetic counseling and cascade screening of relatives. The next paper continues a theme of cardiomyopathy and comes from Derk Frank, Ashraf Yusuf Rangrez, Corinna Friedrich, Sven Dittmann, Norbert Frey, Eric Schulze-Bahr and colleagues from University Medical Center Schleswig-Holstein. In this paper, Cardiac α-Actin Gene Mutation Causes Atrial-Septal Defects Associated with Late-Onset Dilated Cardiomyopathy, the team was interested in understanding the genetics of familial atrial-septal defect. They studied large multi-generational family with 78 family members and mapped a causal variant on chromosome 15q14, which caused nonsynonymous change in exon 5 of the ACTC1 gene. In silico tools predicted this variant to be deleterious. Analysis of myocardial tissue from an affected individual revealed sarcomeric disarray, myofibrillar degeneration, and increased apoptosis. Proteomic analysis highlighted extracellular matrix proteins as being affected. The team over-expressed the mutation in rats and found structural defects and increased apoptosis in neonatal rat ventricular cardiomyocytes and confirmed defects in actin polymerization and turnover which affected contractility. These data implicate the variant in ACTC1 as causing atrial-septal defects and late-onset cardiomyopathy in this family and revealed the underlying molecular mechanisms affecting development and contractility. The next paper is entitled Characterization of the CACNA1C-R518C Missense Mutation in the Pathobiology of Long-QT Syndrome Using Human Induced Pluripotent Stem Cell Cardiomyocytes Shows Action Potential Prolongation and L-Type Calcium Channel Perturbation, and it comes from Steven Estes, Michael Ackerman and colleagues at the Mayo Clinic. They set out to use patient-derived human induced pluripotent stem cells to understand the pathogenicity of a variant in the CACNA1C gene in Long-QT Syndrome. They obtained cells from dermal punch biopsy from an individual with long-QT and a family history of sudden cardiac death who carried an R518C missense mutation in CACNA1C. Starting with fibroblasts, they reprogrammed the cells into iPSCs and then differentiated these into cardiomyocytes. They corrected the mutation back to wild type using CRISPR/Cas9 and then compared the cardiomyocytes carrying the original patient mutation with isogenic corrected cardiomyocyte controls. They found significant differences in action, potential duration, and in calcium handling. Patch clamp analysis revealed increased L-type calcium channel window current in the original mutation-carrying cells in addition to slow decay time and increased late calcium current compared with the isogenic corrected control human iPSC cardiomyocytes. These data strongly suggest that CACNA1C is a long-QT susceptibility gene and demonstrate the potential in using patient-derived iPSCs and CRISPR/Cas9 to understand underlying mechanisms linking variants to disease. The final paper this month is Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor-1 Gene Modulate Guanylate Cyclase Activity and comes from Sara Vandenwijngaert, Chris Newton-Cheh and colleagues on behalf of the CHARGE+ Exome Chip Blood Pressure Consortium, the CHD Exome+ Consortium, the Exome BP Consortium, the GoT2D Consortium, the T2D-GENES Consortium, and the UK Biobank CardioMetabolic Consortium Blood Pressure Working Group. This team wanted to understand how variants in the NPR-1 gene affect the function of the atrial natriuretic peptide receptor-1. They performed a meta-analysis across over 491,000 unrelated individuals, including both low frequency and rare variants in NPR-1 to identify their association with blood pressure. They identified three nonsynonymous variants associated with altered blood pressure at genome-wide significance and examined the function of these variants in vitro. Using cells expressing either wild type NPR-1 or one of the three identified variants, they explored the impact of the variants on the ability of cells to catalyzes the conversion of guanosine triphosphate to cyclic 3′,5′-guanosine monophosphate in response to binding of atrial or brain natriuretic peptide. Increased levels of cyclic GMP are known to decrease blood pressure by inducing by natriuresis, diuresis, and vasodilation. Two variants which associated with high blood pressure in the population meta-analysis were associated with decreased cyclic GMP in response to ANP or BNP in vitro, while one variant which associated with lower blood pressure in humans was associated with higher cyclic GMP production in vitro. These data show that variants affecting loss or gain of function in guanylate cyclase activity could have downstream effects on blood pressure at the population level. That's it for this month. Thank you for listening. We will be back with more next month. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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30 July 2019 10:08

6 years тому10:08

10:08

Jane Ferguson: Hi everyone. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson and this is episode 30 from July 2019. First up we have a paper, the Subtype Specificity of Genetic Loci Associated With Stroke in 16664 cases and 32792 Controls, from Matthew Trailer and colleagues on behalf of the NINDS Stroke Genetics Network and the International Stroke Genetics Consortium. They were interested in understanding whether genetic loci previously found to be associated with stroke have distinct associations with stroke subtypes, specifically ischemic and hemorrhagic stroke. They compiled data sets through an international consortium to analyze 16664 stroke cases and 32792 controls, all of European ancestry. The cases were subtyped using two different stroke classification systems: the Trial of ORG 10172 in Acute Stroke Treatment, or TOAST system, and the Causative Classification of Stroke, or CCS system. They selected genetic loci for consideration based on previous association with stroke in general or stroke subtypes in the MEGASTROKE consortium, which had included a large number of the subjects included in the present study. They used a Bayesian multinomial logistic regression approach to evaluate the association of snips at each locus with stroke subtypes identified under the TOAST and CCS classifications, giving five different case groups compared with a set of controls. 16 loci were taken forward for further analysis. There were seven loci which associated with both ischemic and hemorrhagic strokes subtypes, four which clearly associated with either ischemic or hemorrhagic stroke, with the rest showing less consistent effects. One locus, EDNRA, showed opposite affects for ischemic and hemorrhagic stroke. Overall, the findings indicate a large degree of genetic heterogeneity, but some overlap, suggesting common underlying pathophysiological pathways in different stroke subtypes, potentially related to small vessel disease. More detailed phenotyping and further analysis in large samples is required to fully understand genetic mechanisms underlying the risk of different stroke subtypes. And, just to add, this paper was previously submitted to the pre-print server Bio Archive. We support open science and are always happy to consider papers that have been submitted to pre-print servers. So, if you have a particularly cool paper on Bio Archive that fits our scope, do feel free to send it our way. Next up, we have a paper from Fabiola del Greco, Cristian Pattaro, Peter Pramstaller, Alessandera Rossini, and colleagues, from Eurac Research Institute for Biomedicine. This paper, entitled Lipidomics, Atrial Conduction, and Body Mass Index, Evidence from Association, Mediation, and Mendelian Randomization Models, aims to investigate the mechanisms underlying associations between circulating lipids and atrial conduction. They used mass spectrometry measurement of 151 sphingo- and phospholipids in plasma or serum from individuals who had undergone electrocardiogram measurements to ascertain P-wave duration. They first looked for associations in 839 individuals from the micro islets in South Tyrol, or MICROS study, based in Italy, and replicated in 951 participants of the Orkney Complex Disease Study, ORCADES, based in Scotland. They identified and replicated an association between levels of phosphatidylcholine 38-3 and P-wave duration, which was independent of cholesterol, triglycerides, and glucose levels. However, the association was mediated by BMI, and suggested that increased BMI may cause both increased levels of PC38-3 and longer P-wave duration, suggesting a role for body mass in altered lipids in atrial electrical activity. The next paper is a research letter from Hana Bangash, Iftikhar Kullo, and colleagues from the Mayo Clinic on Use of Twitter to Promote Awareness of Familial Hypercholesterolemia. Scientists and health professionals are increasingly using Twitter to communicate. This team wondered whether organized awareness campaigns, including Twitter events like Tweetathons, really make a different. They analyzed Twitter activity related to familial hypercholesterolemia in September 2018, during national cholesterol education month, which included an international familial hypercholesterolemia awareness day and Tweetathon. They also analyzed tweets from August and October 2018, where there was no formal awareness campaign and compared the FH Twitter activity with that of colorectal cancer, which did not have any formal awareness campaigns at that time. In September, FH-related tweets increased by 152.9% compared to August, and then declined by over 58% in October. The topic reach for familial hypercholesterolemia was 11.1 million in August, and increased over 250% in September to 37.7 million. The reach declined by over 71% in October to just over 10 million. In comparison, the reach for colorectal cancer declined from 453 million in August to 300 million in September and then increased to 677 million in October, which happened to be breast cancer awareness month. These data suggest that awareness campaigns like national cholesterol education month do lead to an increase in Twitter activity. However, this increase isn't necessarily sustained during the following month, and it remains unclear whether Twitter activity actually translates into a wider awareness amongst providers or patients, which could translate into clinical benefits. Nonetheless, as the use of Twitter increases, this may be a promising avenue to promote awareness and to disseminate knowledge. And, of course, I have to take this opportunity to mention that Circulation: Genomic and Precision Medicine is on Twitter and you can follow us @Circ_Gen to keep up with what's going on at the journal. Next up, we have a letter entitled B-iallelic Mutations in NUP205 and NUP210 Are Associated with Abnormal Cardiac Left-Right Patterning from WeiCheng Chen, Yuan Zhang, Sunhu Yang, Xiangyu Zhou, and colleagues from Tongji University. They set out to understand the genetic underpinnings of cardiac left-right patterning and to probe why individuals with situs inversus totalis, or SIT, where the chest organs are in a complete mirror image to typical, have almost no symptoms or complications, while individuals with heterotaxy, who have abnormal organ arrangement that is not a mirror image, typically have severe phenotypes including congenital heart disease. They performed whole exome and whole genome sequencing in 61 family trios with SIT or heterotaxy and identified ballielic missense mutations in nucleoporins NUP205 and NUP210. Nucleoporins comprise the main components of the nuclear pore complex in eukaryotic cells. The team generated induced pluripotent sense cells from peripheral blood cells of an affected patient and a healthy control, and found that there were impairments in protein interactions in the variant cells, particularly interactions with another crucial nucleoporin, NUP93. In zebra fish, NUP205 knockdown resulted in left-right assymetry and defects in heart looping formation in a subset of fish embryos. Knockdown of both NUP205 and NUP93 resulted in impairments in cilia and human retinal pigment epithelial cells. Gene expression analysis revealed affects in known cilia genes NEC2 and NEC3. Overall, this study provides evidence that mutations in nucleoporins NUP205 and NUP210 may cause defects in cardiac left/right patterning, potentially through effects on ciliary function. This issue closes with a letter and response conversation around a recent article on missense mutations in the FLNC gene, causing familial restrictive cardiomyopathy. Hisham Ahamed and Muthiah Subramanian from Amrita Institute of Medical Scientists write to share a case of a woman presenting with features of heart failure and muscular weakness consistent with distal myopathy who was found to carry a deletion in exome 37 of the FLNC gene. This case adds to the previous evidence published by Alvaro Roldan Sofia and Julian Palomino-Doza in March 2019 in our journal, Highlighting Mutations in the FLNC Gene in Cardiomyopathy. That's all for this month. Come back in August for your roundup of the next issue. Thanks for listening! This podcast was brought to you by Circulation: Genomic and Precision Medicine, and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association, 2019.…

Getting Personal: Omics of the Heart

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29 June 2019 13:19

6 years тому13:19

13:19

Jane Ferguson: Hi, everyone. Welcome to episode 29 of Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson from Vanderbilt University Medical Center and an associate editor at Circ: Genomic and Precision Medicine. Let's dive in and see what's new in the June issue. First up, Validation of Genome-Wide Polygenic Risk Scores for Coronary Artery Disease in French Canadians from Florian Wünnemann, Guillaume Lettre and colleagues from the University of Montreal. Polygenic scores have the potential to be used to predict disease risk, but have not been broadly validated in different populations. This team was interested in whether polygenic risk scores that have been found to predict coronary artery disease in European ancestry subjects in the UK Biobank would also predict disease in French Canadians. They calculated two different polygenic risk scores in over 3600 cases and over 7000 controls and tested their ability to predict prevalent, incident and recurrent CAD. Both scores predicted prevalent CAD, but did not perform as well in predicting incident or recurrent disease. This maybe because the majority of subjects were on statant treatment. Overall, the study confirms that polygenic risk scores for CAD developed in European ancestry can be used in other populations of European ancestry. However, further work is needed to develop and validate polygenic risk scores in other ancestries and to explore whether well performing risk scores can be developed to predict incident or recurrent disease. Our next paper comes from Farnaz Shoja-Taheri, Michael Davis and colleagues from Emory University and is entitled Using Statistical Modeling to Understand and Predict Pediatric Stem Cell Function. Stem cell therapy is emerging as a potential therapeutic option for treating pediatric heart failure, which otherwise can only be cured through heart transplantation. The success of stem cell therapy depends on many variables, including the reparative ability of the infused cells. In this paper, the author set out to test whether they could predict the behavior of c-kit+ progenitor cells or human CPCs using RNA seq and computational modeling. They obtained CPCs from 32 patients, including eight neonates whose cells are thought to have the highest reparative capacity, and they performed RNA sequencing. The team had previously developed regression models that could link gene expression data from sequencing to phenotypes in the cells, and they tested these models in the CPC cell lines. They tested seven neonate cell lines in vitro and found that cellular proliferation and the chemotactic potential of condition media matched what was predicted by the RNA seq-based model. They used pathway analysis to identify potential mechanisms regulating CPC performance and identified several genes related to immune response, including interleukins and chemokines. They further confirmed the presence of cytokines at the protein level that were associated with well performing cells showing that at least one of the outcomes could be functionally predicted using an ELISA ASA. This type of approach may prove useful to inform ongoing clinical trials to stem cell therapy in congenital heart disease. The next paper, Systems Pharmacology Identifies an Arterial Wall Regulatory Gene Network Mediating Coronary Artery Disease Side Effects of Antiretroviral Therapy comes to us from Itziar Frades, Johan Björkegren, Inga Peter and colleagues from the Icahn School of Medicine at Mount Sinai. They were interested in understanding mechanisms whereby antiretroviral therapy for HIV leads to increased risk for coronary artery disease. They analyzed the transcriptional responses to 15 different antiretroviral therapy or ART drugs in human cell lines and cataloged the common transcriptional signatures. They then cross-referenced these against gene networks associated with CAD and CAD related phenotypes. They found that 10 of 15 ART response networks were enriched for differential expression and connectivity in an atherosclerotic arterial wall of regulatory gene network identified as causal for CAD. They used cholesteryl ester loaded foam cells in an in vitro model to validate their findings and found that ART treatment increased cholesteryl ester accumulation in foam cells which was prevented when the key network regulator gene, PQBP1, was silenced. Their study highlights a gene network which is altered in response to ART and which promotes foam cells formation, highlighting a mechanistic link between HIV treatment and CAD. Targeting this network potentially through PQBP1 maybe a way to reduce the risk of CAD in individuals treated with antiretroviral drugs. The next paper comes from Brooke Wolford, Whitney Hornsby, Cristen Willer, Bo Yang and colleagues from the University of Michigan and is entitled Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection. They were interested in whether exome sequencing in individuals with thoracic aortic dissection could identify disease associated variance. They conducted exome sequencing in 240 patients and 258 controls and screened 11 genes for potentially pathogenic variance. They identified 24 variance in six genes across 26 cases with no potentially pathogenic variance identified in the controls. They found that carriers of pathogenic variance had significantly earlier age of onset of dissection, higher rates of root aneurysm and greater incidents of aortic disease in family members, while patients without identified variance had more hypertension and a higher rate of smoking. Their study suggests that genetic testing should be considered in patients with thoracic artery dissection particularly in individuals with early age of onset before age 50 and no hypertension with the possibility of cascade screening to follow to identify at risk family members before onset of dissection and possible death. Our next paper is a research letter from Seyedeh Zekavat, Pradeep Natarajan and colleagues from Harvard Medical School, Investigating the Genetic Link Between Arterial Stiffness and Atrial Fibrillation. They aimed to investigate whether arterial stiffness is causal for atrial fibrillation using Mendelian randomization to probe genetic causality. They calculated the genetic component of the arterial stiffness index or ASI, a noninvasive measure of arterial stiffness, in over 131,000 individuals in the UK Biobank. They then assessed whether the genetic predictors of ASI defined as the top six independent variance were also associated with atrial fibrillation in over 225,000 participants in the UK Biobank and in over 588,000 individuals from a multi-ethnic GWAS. They found that the ASI genetic risk score was significantly associated with incident atrial fibrillation in both the UK Biobank and the multi-ethnic AF GWAS. The association held true even after adjustment for age, sex, smoking status, prevalent heart failure, prevalent hypertension, prevalent CAD, prevalent hypercholesterolemia, prevalent diabetes, heart rate, alcohol intake and exercise frequency in the UK Biobank participants. Because some people have hypothesized that atrial fibrillation may actually precede and cause arterial stiffness, the team did the reverse Mendelian randomization experiment and tested whether genetic predictors of AF were associated with the arterial stiffness index. They found no association suggesting that AF does not cause arterial stiffness. In summary, this paper provides genetic evidence supporting arterial stiffness as a causal contributor to atrial fibrillation and suggests that future randomized controlled studies would be warrantied to assess whether methods to reduce arterial stiffness could be protective against atrial fibrillation. The next research letter comes from Scott Damrauer, Kara Hardie, Reed Pyeritz and colleagues from the University of Pennsylvania and is entitled FBN1 Coding Variants and Nonsyndromic Aortic Disease. In this study, the authors were interested in characterizing the frequency of variance associated with Marfan syndrome in the general population. They analyzed data from the Penn Medicine BioBank looking at 12 variance in the FBN1 gene all of which have been reported to associate with Marfan syndrome. Of almost 11,000 individuals who underwent exome sequencing, they identified 70 individuals who were carriers of one of the 12 preselected FBN1 variance. These individuals ranged in age from age 28 to 87 years and 56% of them were male. They combed through clinical data from the participant's electronic health records, including office notes, diagnostic tests and imaging studies. Two individuals had a clinical diagnosis of Marfan syndrome while 21 individuals had evidence of cardiovascular phenotypes related to Marfan syndrome including mitral valve disease, dilated sinus of valsalva, dilated ascending aorta, descending thoracic or abdominal aneurysms or dissections or had undergone surgical procedures involving the mitral valve or thoracic aorta. Compared to age and sex matched controls without known or suspected pathogenic FBN1 variance, the FBN1 variant carriers were significantly more likely to have Marfan syndrome related cardiovascular disease. Although the majority of individuals carrying FBN1 variance did not have documented cardiovascular disease in this study, the data were somewhat limited, meaning that some affected individuals could have been missed. Thus, while the penetrance of these variance appears to be variable, the severe consequences of these FBN1 variance observed in some individuals suggests that clinical screening for carries of these variance is important. To round up this month's issue, we have a scientific statement led by Ferhaan Ahmad and Elizabeth McNally on Establishment of Specialized Clinical Cardiovascular Genetics Programs: Recognizing the Need and Meeting Standards. This statement comes from the American Heart Association Council on Genomic and Precision Medicine, the Council on Arteriosclerosis, Thrombosis and Vascular Biology, the Council on Basic Cardiovascular Sciences, the Council on Cardiovascular and Stroke Nursing, the Council on Clinical Cardiology and the Stroke Council. In this statement, the writing group lays out the importance of establishing specialized centers of care for individuals affected by inherited cardiovascular diseases. As cardiovascular genetics as a field continues to grow and as genomic medicine becomes part of practice, it is essential for programs to evolve to include this new knowledge and specialization. There are significant challenges in interpreting genetic test results and in evaluating counseling and managing the care of genetically at risk family members who have inherited pathogenic variance, but not yet shown signs of disease. Establishing specialized programs to combine cardiovascular medicine and genetics expertise is an effective way to allow for the integration of multiple types of clinical and genetic data and to improve diagnosis, prognostication and cascade family testing in affected individuals and their families. Training individuals in genetic cardiology will allow for improved care and management of risk in affected or at risk individuals and potentially pave the way for genotype specific therapy. This important and timely scientific statement outlines current best practices for delivering cardiovascular genetic evaluation and care in both the pediatric and the adult settings with a focus on team member expertise and conditions that most benefit from genetic evaluation. That's all for this month. Thank you as always for listening and come back next month for the next installment of papers in Genomic and Precision Medicine. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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28 May 2019 12:36

6 years тому12:36

12:36

Jane Ferguson: Hi, everyone. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. It's May 2019, and this is episode 28. So let's see what papers we have in the journal this month. First up, a paper from Mengyao Yu, Nabila Bouatia-Naji and colleagues from the Inserm Cardiovascular Research Center in Paris, entitled GWAS-Driven Gene-set Analyses, Genetic and Functional Follow-Up Suggest Glis1 as a Susceptibility Gene for Mitral Valve Prolapse. In this paper, they set out to characterize the genetic contributions to mitral valve prolapse, or MVP, to better understand the biological mechanisms underlying disease. They applied the gene-set enrichment analysis for QWAS tool and the pathway enrichment tool DEPICT to existing GWAS for MVP in a French sample to identify gene sets associated with MVP. They find significant enrichment of genes involved in pathways of relevance to valve biology and enrichment for gene expression in tissues of relevance to cardiovascular disease. They zeroed in a Glis family zinc finger gene Glis1 with consistently strong pattern of evidence across the GWAS enrichment and transcription analyses. They replicated the association between Glis1 and MVP in a UK biobank sample. They found that Glis1 is expressed in valvular cells during embryonic development in mice, but is mostly absent at later times. They targeted two Glis1 orthologs in zebrafish and found that knockdown of Glis1 B was associated with a significant increase in the incidence of severe atrioventricular regurgitation. These data highlight Glis1 as a potential regulator of cardiac valve development with relevance for risk of mitral valve prolapse. Next up is a paper from Gina Peloso, Akihiro Namuro, Sek Kathiresan and colleagues from Boston University, Kanazawa University, and Mass General Hospital. In their paper, Rare Protein Truncating Variance in APOB, Lower LDL-C, and Protection Against Coronary Heart Disease, the team was interested in understanding whether protein truncating variance in APOB underlying familial hypobetalipoproteinemia confer any protection against coronary heart disease. They sequenced the APOB gene in 29 Japanese families with hypobetalipoproteinemia as well as in over 57,000 individuals, some with early onset CHD and some without CHD. They found that presence of an APOB truncating variant was associated with lower LDL cholesterol and lower triglycerides, and also with significantly lower risk for coronary heart disease. This study confirms that variance in APOB, leading to reduced LDL and triglycerides are also protective against coronary heart disease. : The next paper entitled Mortality Risk Associated with Truncating Founder Mutations in Titin comes to us from Mark Jansen, Dennis Dooijes, and colleagues from University Medical Center Utrecht. They analyzed the effect of titin truncating variance on mortality in Dutch families. Titin truncating variants are associated with dilated cardiomyopathy, but have a very variable penetrance. In this study, the authors looked at three titin truncating variants, established to be founder mutations, and traced the pedigrees back to 18th century ancestors. They looked at 61 individuals on the transmission line and 360 of their first-degree relatives. They find no evidence for excess mortality in variant carriers overall. However, when they restrict it to individuals over 60 years of age, they did find a significant difference in mortality, which was also observed in individuals born after 1965. What these data tell us is that these titin truncating variants have a relatively mild phenotype with effects on mortality only manifesting later in life in many carriers. Given increases in life expectancy over the past several decades, the prevalence of morbidity and mortality attributable to titin truncating variants may increase. Genetic screening may identify genotype-positive, phenotype-negative individuals who would benefit from preventative interventions. Continuing on the theme of genetic variance, we have a paper from John Giudicessi, Michael Ackerman, and colleagues from the Mayo Clinic, Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. In this paper, they aim to find a better way to classify variants of unknown significance, of VUS, in the RYR2 gene. Variants in this gene are commonly associated with catecholaminergic polymorphic ventricular tachycardia, or CPVT. They examined 72 distinct variants in 84 Mayo Clinic cases and find that 48% were classified as VUS under ACMG guidelines. The rate was similar in a second sample from the Netherlands, with 42% of variants originally classified as VUS. They developed a diagnostic scorecard to incorporate a pretest clinical probability of CPVT, which included various clinical criteria, including symptoms and stress test results. Application of the phenotype enhanced ACMG criteria brought the VUS rate down to 7% in Mayo Clinic and 9% in the Dutch samples. The majority of VUS were reclassified as likely pathogenic. This study highlights how incorporation of disease-specific phenotype information can help to improve variant classification and reduce the ambiguity of reporting variants of unknown significance. We also have a number of research letters in the journal this month. From Karine Ngoyen, Gilbert Habib, and coauthors from Marseilles, we have a paper entitled Whole Exome Sequencing Reveals a Large Genetic Heterogeneity and Revisits the Causes of Hypertrophic Cardiomyopathy, Experience of a Multicentric study of 200 French Patients. In this study, they examined the genetic contributions to hypertrophic cardiomyopathy, or HCM, in 200 individuals as part of the HYPERGEN study and compared the benefits of whole exome sequencing compared with targeted sequencing of candidates' sarcomeric genes. All subjects had HCM documented by echocardiography. In the whole exome sequencing data, they first looked for mutations within 167 genes known to be involved in cardiomyopathies or other hereditary diseases. Of these 167 virtual panel genes, they find variants in 101 genes. Following whole exome sequencing, over 87% of the patients had an identified pathogenic, or likely pathogenic, mutation compared with only 35% of patients who only had targeted sequencing of sarcomeric genes. This highlights the generic heterogeneity of HCM and suggests that whole exome sequencing has utility in identifying variants not covered by sarcomeric gene panels. The next letter is from Wouter Te Rijdt, Martin [Vandenberg] and colleagues from University Medical Center Groningen and states that [dissynchronopathy] can be a manifestation of heritable cardiomyopathy. They hypothesized that left bundle branch block, also designated as dissynchronopathy, may be a manifestation of familial cardiomyopathy. They analyzed patients from a database of cardiac resynchronization therapy and identified super-responders whose left ventricular dysfunction was normalized by therapy. They carried out targeted sequencing in 60 known cardiomyopathy genes in 16 of these super-responder individuals and identified several variants, including a pathogenic variant in troponin T in one individual and variants of unknown significance in nine individuals. Pedigree analysis identified multiple family members with dilated cardiomyopathy. This study highlights that dissynchronopathy can be a manifestation of DCM, but that affected individuals may still benefit from cardiac resynchronization therapy. The next letter entitled Targeted Long-Read RNA Sequencing Demonstrates Transcriptional Diversity Driven by Splice-Site Variation in MYBPC3 comes from Alexandra Dainis, Euan Ashley, and colleagues from Stanford University. They set out to understand whether transcriptome sequencing could improve the diagnostic yield over genome sequencing in patients with hypertrophic cardiomyopathy. In particular, they hypothesized that long-read sequencing would allow for identification of alternative splicing linked to disease variance. They used long-read RNA and DNA sequencing to target the MYBPC3 gene in an individual with severe HCM who carried a putative splice-site altering variant in the gene. They were able to obtain heart tissue for sequencing and included several HCM and control subjects in addition to the patient with the MYBPC3 variant. They identified several novel isoforms that were only present in the patient sample, as well as some additional isoforms, including retained introns, extended exons, and an additional cryptic exon, which would not have been predicted based on the DNA variant. While the effects on protein function is not known, the transcripts are predicted to be translated. This analysis highlights the effect of a rare variant on transcription of MYBPC3 and provides additional evidence to link the variant to disease. This is a really nice approach, which could be used to probe causality and mechanisms, not only for cardiovascular disease, but for other rare variants in many disease settings. We finish with a perspective piece from Nosheen Reza, Anjali Owens, and coauthors from the University of Pennsylvania entitled Good Intentions Gone Bad, The Dangers of Sponsored Personalized Genomics. They present a case of a 23-year-old woman who presented for genetic counseling and evaluation after discovering she carried a likely pathogenic MYH7 variant associated with cardiomyopathy. She had no significant medical history, but had participated in employer-sponsored genetic testing motivated to identify potential variants related to cancer given a family history of cancer. After receiving her results, she experienced considerable anxiety and stopped exercising out of fear of cardiac complications. She visited an ER after experiencing chest pain, something she had not experienced previously. There was no appropriate counseling available at her institution for her genetic test results, leading her to seek out the additional counseling. Thus, while she was initially motivated to complete genetic testing because her employer offered it free of change, she ended up incurring costs related to the followup evaluation and counseling. Ultimately, she had no significant clinical findings. Although the variant had been listed as likely pathogenic, other sources consider it to be of unknown significance. This story highlights the psychological and financial impact that genetic testing can have on individuals, particularly when carried out without any pretest counseling or accessible post-test support when variants are identified. Despite the considerable promise of personalized medicine, there are many complexities to be considered, particularly with direct-to-consumer testing and employer-sponsored testing. This perspective highlights the ethical considerations and urges caution to maintain the best interests of patients. That's all for this month. Thanks for listening. I look forward to bringing you more next month. This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

1
27 April 2019 24:26

6 years тому24:26

24:26

Jane Ferguson: Hello and welcome to Getting Personal: Omics of the Heart, your podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson from Vanderbilt University Medical Center, and this is episode 27 from April 2019. This month, I talk to Riyaz Patel, the first author on not one, but two articles published this issue, presenting analyses from the GENIUS-CHD consortium. But before we get to the interview, let's review what else was published this month. First up, we have a paper from Tamiel Turley, Timothy Olson and colleagues from the Mayo Clinic, entitled Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection. In this study, the authors were interested in identifying novel susceptibility genes for spontaneous coronary artery dissection or SCAD, which predominantly affects young women who appeared otherwise healthy. They conducted whole exome sequencing in a family with three affected family members and found a rare missense variant in the TLN1, or talin 1, gene. This gene encodes the talin protein which is part of the integrin adhesion complex linking the actin cytoskeleton to the extracellular matrix. This gene and protein is highly expressed in coronary arteries. They went on to sequence additional sporadic cases of SCAD, and they found additional talin 1 variants in these individuals. While there was evidence for incomplete penetrance, these data implicate TLN1 as a disease-associated gene in both familial and sporadic SCAD. The next paper comes from Miroslaw Lech, Jane Burns, and colleagues from UCSD School of Medicine and Momenta Pharmaceuticals and is entitled Circulating Markers of Inflammation Persist In Children And Adults With Giant Aneurysms After Kawasaki Disease. Kawasaki disease is the most common cause of acquired pediatric heart disease, but disease progression can vary a lot, and it's likely modulated by complex gene-environment interactions. Coronary artery aneurysms occur in about 25% of untreated patients, but early treatment with intravenous immunoglobulin or aspirin reduces the risk for these aneurysms to 5%, suggesting an important role for inflammation. In this study, the authors applied shotgun proteomics, transcriptomics, and glycomics on eight pediatric Kawasaki disease patients at the acute, subacute, and convalescent time points. They identified inflammatory profiles characterizing acute disease which resolved during the subacute and convalescent time points, except for in the patients who went on to develop giant coronary artery aneurysms. They went on to carry out proteomics on nine Kawasaki disease adults with giant coronary artery aneurysms and matched healthy controls, and they confirmed the inflammatory profiles in the adult samples. In particular, calprotectin, which is composed of S100A8 and S100A9, was elevated in the plasma of patients with CAA, an association they confirmed in additional samples of pediatric and adult Kawasaki disease patients and healthy controls. These data suggest that calprotectin may serve as a biomarker of ongoing inflammation in Kawasaki disease patients following acute illness, and may be able to identify individuals at increased risk of aneurysms. Next up, we have a research letter, Heart BioPortal: An Internet-of-Omics for Human Cardiovascular Disease Data, from Bohdan Khomtchouk, Tim Assimes, and colleagues from Stanford University. They had noticed that, in contrast to the field of cancer research, there were no open access platforms for cardiovascular disease data that offered users the ability to visualize and explore high quality data. They set out to fix this and developed the Heart BioPortal, which is accessible at www.heartbioportal.com. This portal allows the user to integrate existing CDD related omics data sets in real time and provides intuitive visualization and analyses in addition to data downloads. The primary goals are to support gene, disease, or variant-specific request, and to visualize the search results in a multi-omics context. They currently collate gene expression, genetic association, and ancestry allele frequency information for over 23,000 human genes and almost 6,000 variants across 12 broadly defined cardiovascular diseases spanning 199 different research studies. And this is just the start, they're hoping to add more studies, more data, and functionality for querying CDD drug targets, along with lots more. This is a really great resource which will no doubt be of real value to the community. I urge you to go online, check it out, put in your favorite gene, and see what you find. Riyaz Patel, Folkert Asselbergs, and many, many collaborators published Subsequent Event Risk in Individuals With Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium and Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study Of Individual Participant Data. These papers present the design of the genetics of subsequent coronary heart disease, or GENIUS-CHD consortium, which was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events in individuals with established CHD. The consortium currently includes 57 studies from 18 countries, recruiting over 185,000 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed up study participants prospectively for subsequent events. Enrollment into the individual studies took place between 1985 to the present day, and the duration of follow-up ranges from nine months to 15 years. Participants have mostly European ancestry, are more likely to be male, and were recruited between 40 to 75 years of age. In their first analysis using these data, they investigated whether the established 9p21 locus associated with subsequent events in individuals with established coronary heart disease. Confirming previous smaller studies, they showed that while genotype at 9p21 is associated with coronary disease when compared to healthy controls, 9p21 genotype is not associated with a risk of future events in people who already have coronary disease. Dr. Patel joins me to tell me more about the GENIUS-CHD consortium and the analyses described in these papers. Today, I'm joined by Dr. Riyaz Patel, who's an associate professor at University College London and a cardiologist at the Barts Heart Centre in London. Dr. Patel, thank you so much for joining me. Dr. Riyaz Patel: Pleasure to be on, thanks. Jane Ferguson: So, as we're going to discuss, you are the lead author on two back-to-back publications that were published in Circ Gen this month exploring genetic predictors of coronary heart disease as part of the GENIUS-CHD consortium. Before we delve fully into them, could you tell us a little bit about your background and how you got into this research field? Dr. Riyaz Patel: Yes. I'm an academic cardiologist, as you know, and I first got into genetics of coronary disease about 12-13 years ago, now, around the time that genome wide association studies were about to take off, or were taking off. I studied, I worked at Emory University, in fact, in Atlanta, in the US. We had a very big cohort of patients who had coronary disease, who were undergoing coronary angiography. At that time, we were doing quite a lot of genetic association studies and biomarker work in patients with heart disease. One of the key problems we often encountered was sort of looking for replication cohorts and trying to do things at a bigger scale than what we had available. So that kind of really was the initial driver for trying to bring together a bigger collaboration to take that sort of work to the next level. Jane Ferguson: It sounds like you've got valuable expertise, because looking at the author list for these papers, I think it's one of the longest author lists I've ever seen. It's a huge endeavor. I'd love to hear more about how that got started and how you managed to build this consortium, and you know, and tell us what the consortium actually is. Dr. Riyaz Patel: Yeah, it's been a labor of love. And essentially, I started when I returned back to the UK and we were looking to develop this further. We had already collaborated with several colleagues in the US and abroad from my time at Emory. So, we pulled together a small group of people who we were already working together with and then we did predicts of systematic searches of literature to identify cohorts who were also doing similar things. Again, investigating people with heart disease and looking at subsequent event risk. So, we did that and then we systematically approached, very much, as many people as we could find and over the course of the last, maybe 3 or 4 years, we've brought together a small community of collaborators around the world, and as you rightly said, it's a very long list. In total, we're counting around 180 or so investigators. But, in a way, that also speaks to how this consortium is not just a collection of studies. It is a collection of people and a lot of expertise was brought to the table because of that. People have been thinking about these questions for many, many years and this platform essentially is an opportunity for everyone to share that knowledge. Dr. Riyaz Patel: So that's kind of how the consortium started and is being pulled together. We operate on a sort of loose memorandum of understanding where every member of the consortium is free to participate in studies as they wish. We run analysis in a federated way which means that [inaudible 00:10:50] scripts are shared and people standardize their data and then they run analyses locally and they only share summary level data so that obviously overcomes the big governance hurdle. So, that's pretty much how the consortium works at moment. Jane Ferguson: Yeah. I'm sure there was probably a lot of challenges along the way in figuring this out and getting scripts that work for everybody, dealing with all the people, so how do you do this? Do you have regular phone calls with 180 people on it? Do you have lots and lots of emails? Dr. Riyaz Patel: (laughs) Jane Ferguson: How's it actually working? Dr. Riyaz Patel: So, we have a steering committee which is represented by at least one person from each study. So, that limits the number of people down to about, a more manageable number, about 50 or 60. And we do have regular teleconferences, particularly in the early days when we were still pulling everything together. Now, we try and meet at least once a year, if not twice at year at the major conferences, at the European Site of Cardiology and one of the big American meetings, ACC or AHA, so that's usually a good face to face meeting that we have with everyone and then as with all consortia, we have regular email lists and contact through that means. Jane Ferguson: So, now that you've got everybody together, you have over 185,000 participants as part of this from 18 different countries. So, how have you been able to use all of these different data and harmonize the different phenotypes and sort of put everything together to actually run the analyses. Dr. Riyaz Patel: The way we started off is by asking everyone to share almost an inventory of what they have collected. We then sought to try and standardize all of the core variables: age, sex, smoking and so forth. Once we were happy about the key variables had been standardized, units were the same and so forth, we then created, effectively a GENIUS-CHD data set that each cohort had curated. So, this was the main way of harmonizing the data set. Now, obviously, there are a lot of other differences between each of these studies. So, we have within the consortium a combination of different studies. We have randomized clinical trials, we have cohort studies, we have nested cohorts from larger population studies and we try and, in all of the analyses, we have pre specified subgroup analyses to try and look out and check for any heterogeneity that is introduced because of all of this. But the biggest, sort of, difference that we have factored in is that each of these studies collects patients with different types of coronary heart disease. Dr. Riyaz Patel: So, there are about ... 40% or so are acute coronary syndrome recruited patients, where these people are recruited at the time or after their acute event. And a similar proportion are recruited when they're much more stable. So, in all of our analyses we do try and factor in the differences in terms of the type of CHD patients are enrolled with but everything else, as best as we can, we have tried to standardize including all of the outcomes. So, for example, we share the ICD codes that would define a particular type of outcome across all the different cohorts, so even if you're in a different country, they will generally be reasonably well standardized. Jane Ferguson: Mm-hmm (affirmative), yeah, yeah. I think it's important and I can see the pros and the cons, you know, you have more diversity and you're representing a broader spectrum of disease by including everybody but then, of course, it's hard to figure it out, but I'd say it gives you a lot of versatility with the types of analyses you can do. Jane Ferguson: As we mentioned, there's two papers so people can go online and read those two papers. And the first one, is sort of the design and goes really into detail of how you guys set this up and I think is a really nice, sort of, example of, if anybody else was trying to (laughs) do something like this, of how to follow it. But then you also did, sort of, an initial analysis, right, to show what this consortium can actually do. I looked at 9p21, so I'd love to hear more about those analyses. Dr. Riyaz Patel: Yeah, so 9p21 is one of the most reproduced variants with coronary disease across the world. And it's remarkable how well replicated it's been in all sorts of settings in different countries. But the key thing is that it's been associated mostly in case controlled studies or in first event type of studies. And when we looked at this question some years ago now, at whether a variation of chromosome 9p21 is also associated with subsequent events, IE., we could test in people who've already had a heart attack or coronary disease, does it predict a worse outcome for them. We found that it hadn't. Dr. Riyaz Patel: [inaudible 00:16:06] was in the literature metro analyses and, sort of, all the caveats that come with that. So, we thought that as a feasibility analysis within the consortium, "why don't we also look at 9p21," which we did and this time around, we were able to identify that 93,000 people with coronary heart disease who had our primary endpoint of coronary heart disease death or MI subsequent to other index events. Again, we confirmed our previously met analyses findings that in this particular setting, 9p21 doesn't seem to associate with risk of subsequent events. And that sort of fits with our understanding of 9p21 so far. And interestingly, in one of our analyses, we identified that it does associate with risk of repeat revascularization. And from what we know about 9p21 so far, it seems to associate with risk of atheroma development or progression as opposed to perhaps plaque vulnerability or rupture which might give you an acute coronary event. Dr. Riyaz Patel: So, it's been a good example, I think, and really an illustration of how this consortium can work at scale. We have a lot of flexibility in terms of different subgroups that we can look at. And we really drilled down in this paper at all the possible reasons why a neutral finding may have occurred. We've looked at selection bias, we've looked at all the different subgroups which was can do because of the scale of the analysis. So, yeah, so that's kind ... it's really, the findings are not particularly novel in their own right but it is a very good example of feasibility of a consortium. Jane Ferguson: Yeah, I agree. Because it is, so often, if you get, sort of, a negative finding, you keep wondering, "Well, was it just the power? Do we not ... are we not able to find it?" But, I think, with the scale that you have, you're really able to drill down and say, "Look, we really think there's nothing here. It's a true negative finding." You know, 9p21 is not associated with subsequent events, although, I think the revascularization is interesting and that can, sort of, inform, I guess, more basic research into the the mechanisms of 9p21. Dr. Riyaz Patel: Exactly. Exactly. Jane Ferguson: So, what's next? I'm sure there's a lot more papers and analyses that are, sort of, to come out of this. So, can you give us, sort of, a sneak peek of what you're working on now? Dr. Riyaz Patel: Yeah, so, like with 9p21, we did have a selection of variants to answer important questions. So, for example, we were looking at the role of PCSK9 variation to try and see how that relates in this particular setting, given that trials have already reported on the effective drug. And similarly, we're also looking at interlinking six receptor blockade as a, sort of, similar sort of [inaudible 00:19:11] randomization study to look at the validity of a drug target in a secondary prevention setting. Dr. Riyaz Patel: Beyond that, we are looking at genome wide association studies and, hopefully, once that is done, the consortium will be in a position to do lots of quick look-ups or all sorts of different questions in genetic variation to inform drug target analyses. So, those are immediate priorities, but we are also, in parallel, looking at non-genetic analyses, so, once again, there are lots of standard clinical risk factors that we need to explore a bit more thoroughly in this setting. So as you're aware, there are various paradoxes that keep creeping up in studies where patients have coronary heart disease already, so the obesity paradox is a good example. And what we're hoping to do, is we're hoping to drill down into many of these observational findings in this particular setting, which hasn't really been done, simply again, because the lack of available resources of anything at this scale. Jane Ferguson: It's exciting and it sounds like you have a really powerful set of different data sets to be able to ask a lot of interesting questions. So, I'm excited to see what's gonna come out next. Dr. Riyaz Patel: The other key thing we're working on is also about risk prediction. So, again, one of the things we're missing in the clinical community is good risk prediction tools for subsequent event risk among patients with heart disease. We are working with various colleagues to try and develop better risk prediction algorithms for people who've survived coronary event or have coronary disease. Jane Ferguson: Alright, that's really interesting and that feeds in really nicely then to, sort of, the precision medicine approach. Well, congratulations on building this. I think that's a huge effort in itself and then also in these two papers that were published this month. I think it's really, really, really great work. Dr. Riyaz Patel: Well thank you. And a key message here is that we want to build and expand this community of investigators around the world who are looking at risk question because individually, I think, we've all struggled with various, sort of, issues. But collectively, I think we have so much more potential to really address some big questions. And the consortium, as I mentioned, is not just investigator led in terms of what we're doing. We're also very open to collaboration and for people wishing to replicate their own findings and are looking for similar cohorts or larger scale validation opportunities so that is also another key advantage in benefit or risk consortium. Jane Ferguson: Well, that's wonderful. So, if anyone has either data sets that they want to contribute, are you still, sort of, accepting new investigators? Dr. Riyaz Patel: Absolutely. Very much so. I mean, in the paper, we do mention that we are limited, particularly in terms of cohorts that are enriched for female patients as well as cohorts enriched for patients who are non-Caucasian, in terms of ethnicity. Because, again, those are important patient groups that we need to address. But, generally speaking, we are absolutely open to including anyone who's interested and who meets the inclusion criteria which is collecting people with coronary heart disease, have got genotyping or examples stored for future analysis and have prospective outcomes connected. Jane Ferguson: And is there a minimum size of sample that somebody needs to participate? Dr. Riyaz Patel: Ideally, we'd like to, sort of, set that level at about 1,000 recruited patients. But again, if someone has a very deeply phenotyped cohort and that are interested, we'd be more than happy to discuss that and take that to the steering group. Jane Ferguson: Okay, wonderful. So, people can just email you if they wanna contact- Dr. Riyaz Patel: Absolutely. Jane Ferguson: You any further. Dr. Riyaz Patel: We also have a website, which is for the consortium, which also has contact details on there. Jane Ferguson: Okay, perfect. Alright, so let me see. Your email is riyaz.patel@ucl.ac.uk- Dr. Riyaz Patel: Right. Jane Ferguson: And then the website for the consortium? Dr. Riyaz Patel: Www.genius-chd.org Jane Ferguson: Okay. Perfect. Thank you. So, any listeners that are interested, we'll urge them to either go to the website, read some more, go read the papers, email you directly to talk more. Thank you so much for joining me and for talking about this work. Dr. Riyaz Patel: Thank you for having me. Jane Ferguson: That's it for April. Come back in May for the next issue. And thank you for listening. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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26 March 2019 11:48

6 years тому11:48

11:48

Jane Ferguson: Hello, and welcome to episode 26 of Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine . I'm Jane Ferguson. It's March 2019, and I'm ready to spring into this month's papers, and apparently make really bad seasonal related jokes. Sorry all. Okay, let's get started. First up, is a paper from Oren Akerborg, Rapolas Spalinskas, Sailendra Pradhananga, Pelin Sahlén and colleagues from the Royal Institute of Technology in Solna, Sweden entitled "High Resolution Regulatory Maps Connect Vascular Risk Variants to Disease Related Pathways." Their goal was to identify non-coding variants associated with coronary artery disease, particularly those with putative enhancers and to map these to changes in gene function. They generated genomic interaction maps using Hi-C chromosome confirmation capture, coupled with sequence capture in several cell types, including aortic and ethelial cells, smooth muscle cells and LPS stimulated THP-1 macrophages. They captured over 25,000 features and they additionally sequenced the cellular transcriptomes and looked at epigenetic signatures using chromatin immunoprecipitation. They looked at regions interacting with gene promoters and found significant enrichment for enhancer elements. Looking at variants previously implicated in genome-wide associated studies, they identified 727 variants with promoter interactions and they were able to assign potential target genes for 398 GWAS variants. In many cases, the gene associated with a particular variant was not the closest neighbor, highlighting the importance of considering chromatin lupane when assigning intergenic variants to a gene. They identified several variants that interacted with multiple promoters, influencing expression of several genes simultaneously. Overall, this paper is a great resource for the community and takes many of these GWAS hits to the next level in starting to understand their biological relevance. They have a lot of supplemental material available online so it's definitely worth checking that out and taking a look for your favorite non-coding variant or chromosomal region to see if you can get some more information on it. Next up, Pierrick Henneton, Michael Frank and colleagues from the Hopital Europeen Georges-Pompidou in Paris bring us "Accuracy of Clinical Diagnostic Criteria For Patients with Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Center." The authors were interested in determining the accuracy of the diagnostic criteria used to select patients for genetic testing for suspected vascular Ehlers-Danlos syndrome. This is because, despite the Villefrench criteria being recommended for diagnosis, the accuracy of the diagnostic criteria was never formally tested. They selected 519 subjects, including 384 probands and 135 relatives who had been seen between 2001 and 2016. They assessed the sensitivity and specificity of the Villefrench classification. Almost 32% of tested individuals carried a pathogenic COL3A1 variant. The sensitivity of the Villefrench criteria was 79% with a negative predictor value of 87%. Symptomatic probands had the highest accuracy at 92% sensitivity and 95% negative predictive value. However, the specificity was just 60%. Applying revised diagnostic criteria from 2017, it was actually less accurate because even though there was an increase in specificity, the sensitivity was reduced. Overall diagnostic performance was worst in individuals under 25 and neither set of diagnostic classifications allowed for early clinical diagnosis in individuals without a family history. Our next paper is a Mendelian randomization analysis from Susanna Larsson, Stephen Burgess and colleagues from Uppsala University and the University of Cambridge. This paper entitled "Thyroid Function And Dysfunction In Relation to Sixteen Cardiovascular Diseases: A Mendelian Randomization Study" aims to understand how subclinical thyroid dysfunction relates to risk of cardiovascular diseases. They generated genetic predictors for thyroid stimulating hormone, or TSH, through a GWAS meta-analysis in over 72,000 individuals. They then analyzed the association of genetically predicted TSH with cardiovascular outcomes in large GWAS studies of atrial fibrillation, coronary artery disease, and ischemic stroke, and further assessed associations with phenotypes in the UK Biobank. They found genetically decreased TSH levels and hyperthyroidism were associated with increased risk of atrial fibrillation but not other tested phenotypes. Overall, these data support a causal role for TSH and thyroid dysfunction in atrial fibrillation but not in other cardiovascular diseases. The next paper is also a Mendelian randomization analysis from members of the same group, Susanna Larsson, Stephen Burgess and colleagues published "Resting Heart Rate and Cardiovascular Diseases: A Mendelian Randomization Analysis." In this letter, they describe a study of the relationship between genetically increased resting heart rate and cardiovascular diseases. They constructed genetic predictors of resting heart rate and similarly to the previous study, used that as an instrument to test for associations with coronary artery disease, atrial fibrillation, and ischemic stroke in the cardiogram, atrial fibrillation, and mega stroke consortia respectively. They also looked at 13 CVD outcomes in the UK Biobank. They found that genetically predicted heart rate was inversely associated with atrial fibrillation with suggestive evidence for an inverse association with ischemic, cardioembolic, and large artery stroke. The inverse association with AF was replicated in the UK Biobank, supporting previous reports linking resting heart rate to atrial fibrillation. Next up, we have a letter from Robyn Hylind, Dominic Abrams, and colleagues from Boston Children's Hospital. This study entitled "Phenotypic Characterization of Individuals with Variants in Cardiovascular Genes in the Absence of a Primary Cardiovascular Indication For Testing" describes their work to probe incidental findings for potential cardiovascular disease variants in individuals undergoing clinical genomic sequencing for non-cardiac indications. They included 33 individuals who had been referred as carrying variants that were indicated as being associated with cardiovascular disease in primary or secondary findings. The variants were reclassified using the 2015 ACMG guidelines, and then were compared to the original classification report obtained at the time of sequencing. Of 10 pathogenic or likely pathogenic variants, only four of these were actually considered pathogenic or likely pathogenic after reclassification under the 2015 ACMG criteria, and none of these were associated with a cardiac phenotype. None of the variants could be definitively linked to any cardiac phenotype. The costs ranged from $75 to over $3700 per subject with a cost per clinical cardiac finding estimated at almost $14,000. This study highlights the relatively high cost and low yield of investigating potential cardiovascular variants and prompts consideration of how to implement strategies to ensure that variant reporting maximizes clinical return but minimizes the financial, time, and psychological burdens inherent in lengthy follow-ups. The next paper is a clinical letter from Serwet Demirdas, Gerben Schaaf and colleagues from Erasmus University Rotterdam entitled "Delayed Diagnosis of Danon Disease in Patients Presenting with Isolated Cardiomyopathy." They report on a clinical case of a 14-year-old boy presenting with cardiac arrest due to ventricular fibrillation during exercise. Echocardiography and MRI showed cardiac concentric hypertrophy, particularly in the left ventricle. The boy's mother had died at age 31 after being diagnosed with peripartum dilated cardiomyopathy. Sequencing in the boy revealed a variant in the LAMP2 gene, known to be responsible for Danon disease, which typically presents as cardiomyopathy, skeletal myopathy, and intellectual disability. This same LAMP2 variant was found in preserved maternal tissue, but not in other family members. In this case, there was no evidence of muscle or intellectual abnormalities. However, sequencing had allowed for this diagnosis of Danon disease in the child and posthumously in his mother. This study demonstrates a utility of using extended gene panels in clinical sequencing to aid in diagnosis and to inform management of patients. The next letter is from Alvaro Roldan, Julian Palomino-Doza, Fernando Arribas and colleagues from University Hospital of the 12th of October in Madrid and is entitled "Missense Mutations in the FLNC Causing Familial Restrictive Cardiomyopathy: Growing Evidence." This report also highlights clinical cases. In this case, two individuals with variants in the filamin C, or FLNC gene. Two unrelated individuals presenting with restricting cardiomyopathy were sequenced and found to carry two different variants in the FLNC gene, one of which had not been previously reported. This expands the number of reported cases of filamin C mutations in restrictive cardiomyopathy and highlights the need for further study of the pathophysiology linking filamin C to cardiac function. Finally, we have some correspondence related to a previously published article. In the letter, Christopher Chung, Briana Davies, and Andrew Krahn comment on the recently published article from Jody Ingles on concealed arrhythmogenic right ventricular cardiomyopathy in sudden unexplained cardiac death events. In that paper earlier this year, they had reported on four cases of individuals presenting with cardiac arrest or sudden cardiac death, attributable to concealed arrhythmogenic right ventricular cardiomyopathy with underlying mutations in the plakophilin-2 gene. In the letter from Chung et al, they report similar findings where individuals may first experience electrical phenotypes before manifesting structurally detectable disease. Indeed, in their response to this letter, Ingles et al report identification of an additional case since publication of their original article. Taken together, this further strengthens the case for development of additional strategies to identify at risk individuals and predict and prevent disease events. That's all for the papers for March 2019. Go online to check them out and follow us on Twitter @Circ_Gen to see new papers as they are published online. Thanks for listening. Until next month everyone. This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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25 February 2019 12:44

6 years тому12:44

12:44

Jane Ferguson: Hi everybody. Welcome to Episode 25. I'm Jane Ferguson. This is Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine , and it is February 2019. Let's get started. The first paper this issue is a concurrent publication and comes to us from 29 different editors-in-chief of 27 major cardiovascular journals, led by Joseph Hill, editor-in-chief of Circulation. This editorial, entitled Medical Misinformation: Vet the Message! gives a pointed reminder of the real life risks of misinformation that spreads rapidly through social media and influences people who are making crucial decisions about healthcare for themselves and their families. Quoting directly from the paper they say, "We, the editors-in-chief of the major cardiovascular scientific journals around the globe, sound the alarm that human lives are at stake. People who decline to use a statin when recommended by their doctor, or parents who withhold vaccines from their children, put lives in harm’s way." In this editorial they call on those in the media to do a better job of taking responsibility for the information they disseminate. In particular, in evaluating content before disseminating it, and avoiding false equivalencies where overwhelming scientific evidence favors one side of the so called "debate." I'll add to that that those of us who are medical or scientific professionals need to do our best to take the time to explain our science to those around us. The science underlying most of medicine is complex and hard to explain and sometimes incomplete, but we do a disservice to people if we don't at least try. Let's all join the editors in calling everyone to vet information and hold those with power in the media accountable for the spread of misinformation they enable. Next up this issue, a paper from Jody Ingles, Birgit Funke, and co-authors from the University of Sydney, Harvard Medical School and others, entitled Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes. As panels for clinical genetic testing expands to include more genes, there are more and more variants that are detected and reported to patients, but do not necessarily have underlying evidence to support or disprove pathogenicity. This group aimed to systematically assess the validity of potential gene disease associations with hypertrophic cardiomyopathy and left ventricular hypertrophy by curating variants based on multiple lines of genetic and experimental evidence. They categorized genes based on the strength of evidence of disease causation and reviewed HCM variant classification in the ClinVar variant and phenotype repository. They selected 57 genes to study based on those which were frequently included on test panels or had previous reports of association with HCM. Of HCM genes, only 24% were characterized as having definitive evidence for disease causation, 10% of the genes had moderate evidence, while 66% had limited or no evidence for disease causation. Of syndromic genes, 50% were definitively associated with left ventricular hypertrophy. Of over 4,000 HCM variants in ClinVar, 31% were in genes that, on review, had limited or no evidence for association with disease. What this study shows is that many genes that are included on panels for diagnostic testing for HCM actually have little evidence for any relationship to disease. Systematic curation is required to improve the accuracy of information being acquired and reported to patients and families with HCM. Moving on to the next paper. This manuscript describes the international Triadin Knockout Syndrome Registry: The Clinical Phenotype and Treatment Outcomes of Patients with Triadin Knockout Syndrome. It comes from Daniel Clemens, Michael Ackerman and colleagues from the Mayo Clinic. So, Triadin Knockout Syndrome is a rare inherited arrhythmia syndrome and it is caused by recessive null mutations in the cardiac triadin gene. To improve the ability to study this rare syndrome, this group established the International Triadin Knockout Syndrome Registry, with the goal of including patients across the world with homozygous or compound heterozygous triadin null mutations. The registry currently includes 21 patients from 16 families who have been carefully phenotyped and many of whom exhibit T wave inversions and have transient QTC prolongation. The average age for first presentation with cardiac arrest or syncope was three years of age. Despite a variety of treatments, the majority still have recurrent breakthrough cardiac events. These data highlight the importance of conducting testing for triadin mutations in patients, particularly young children presenting with cardiac arrest, and as this registry grows it will enable a better understanding of the disease and hopefully pave the way for future triadin gene therapy trials. The next paper comes from Daiane Hemerich, Folkert Asselbergs and colleagues from Utrecht University, and is entitled Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes. They were interested in whether variants that have been associated with myocardial mass may exert their influence through regulatory elements. They analyze the hearts of hypertrophic cardiomyopathy patients and non-disease controls and ran ChIP-seq in 14 patients and 4 controls and RNA-seq in 11 patients and 11 controls. They selected 52 loci that have been associated with electric cardiogram defined abnormalities in amplitude and duration of the QRS complex and looked specifically at these gene regions. They found differential expression of over 2,700 different genes between HCM and control. They further found differential acetylation over 7,000 regions. They identified over 1000 super enhancers that were unique to the HCM samples. They found significant enrichment for differential regulation between disease and control hearts within the loci previously associated with HCM, compared with loci not associated with HCM. They analyzed regions where putative causal SNPs overlapped regulatory regions, and identified 74 co-localized variants within 20 loci, with particular enrichment for SNPs in differentially expressed promoters. They confirmed associations with 18 previously implicated genes, as well as identifying 14 new genes. Overall, what this study demonstrates is that by looking at regulatory features that differ in affected tissues between disease and healthy individuals, we can learn more about the underlying mechanisms of disease. Moving on, we have a paper entitled Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates from Ellie Paige, Marc Clément, Daniel Freitag, Dirk Paul, Ziad Mallatt and colleagues from the University of Cambridge. They aimed to investigate a specific SNP in the Interleukin-6 receptor rs2228145, which has been associated with abdominal aortic aneurysms. Inflammation is thought to be a contributor to aneurism progression. The authors hypothesized that the IL-6 receptor's SNP may affect aneurysm growth. They use data from over 2,800 subjects from nine different prospective cohorts and examine the effect of genotype on annual change in aneurysm diameter. Although there was a significant association between genotype and baseline aneurysm size, there was no statistically significant association with growth over time. It appeared that growth was less in minor allele carriers, but the effect if true, was small and the analyses were not powered for small effect sizes. Sample sizes are limited for cohorts with abdominal aortic aneurysms and the authors already used all available worldwide data. In complimentary experiments in mice, they examined the effect of blocking the IL-6 receptor pathway. They found that selective blockage of the IL-6 trans-signaling pathway mediated by soluble IL-6 receptor was associated with improved survival in two different mouse models. However, blocking the classical membrane-bound IL-6 signaling pathway in addition to the trans-signaling pathway did not lead to improved survival. Although the severe lack of enough subjects for well powered genetic analyses is a major limitation for the study of abdominal aortic aneurism and humans, this paper demonstrates the potential relevance of the IL-6 trans-signaling pathway and aneurysm growth, and suggests that further interrogation of this pathway may be informative in figuring out new ways to prevent aneurysm progression and rupture. Next, we have the first of two research letters this issue. The letter on Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation comes to us from Marcus Dorr, Renate Schnabel and co-authors from several institutions including University Heart Center in Hamburg. They were interested in gaining a better understanding of the genetics underlying vascular function. They ran a meta-analysis of brachial artery diameter, maximum brachial artery diameter adjusted for baseline diameter, and flow-mediated dilation in over 17,000 individuals of European ancestry from six different GWA studies. They sought to replicate findings in over 9,500 newly genotyped individuals. They identified two novel SNPs for baseline brachial artery diameter, but no SNPs reached significance or replication from maximum brachial artery diameter or flow-mediated dilation. One of the significant SNPs was located in the insulin-like growth factor binding protein 3, or IGFBP-3 gene. They analyzed plasma IGFBP-3 protein levels in 1,400 individuals and found a significant association with brachial artery diameter. The second SNP they identified is located within the AS3MT gene for arsenite methyltransferase, and this SNP appears to be an eQTL for AS3MT expression in monocytes and arterial tissue. Along with identifying these two genes with potential involvement in baseline brachial artery diameter, this study also supports a low genetic component to flow-mediated dilation, indicating that environmental factors may be or more influential in FMD. The final research letter comes from Alexis Williams, Craig Lee and colleagues from the University of North Carolina and is entitled CYP2C19 Genotype-Guided Antiplatelet Therapy and 30-Day Outcomes After Percutaneous Coronary Intervention. It is known that loss of function variants in CYP2C19 effect bioactivation of clopidogrel, and CYP2C19 genotyping is increasingly used to guide antiplatelet therapies. The authors were interested in whether genotype-guided therapy is effective in reducing major adverse cardiovascular events in the short term, specifically in the 30 days following percutaneous coronary intervention, when most MACE occurs. They followed over a thousand individuals undergoing PCI and CYP2C19 testing and looked at atherothrombotic and bleeding outcomes. Consistent with implementation of genotype-guided therapy, individuals carrying loss of function alleles were less likely to be prescribed clopidogrel. However, out of loss of function carriers, those who did take clopidogrel had significantly higher risk of MACE with no difference in bleeding risk. There was no difference by therapy in individuals without a loss of function allele. What this study shows us is that even in the 30 days following PCI, genotype-guided therapy can be effective in protecting individuals carrying loss of function CYP2C19 variants. And that's it from us for February. Go online to ahajournals.org/journal/circgen to read the full papers, access videos and more, and of course to delve into the podcast archives. Thank you for listening and I look forward to bringing you more next month. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.…

Getting Personal: Omics of the Heart

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23 December 2018 5 31:12

6 years тому31:12

31:12

Jane Ferguson: Hello, everyone. Welcome to Episode 23 of Getting Personal, Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine . It's December 2018. I'm Jane Ferguson. So let's get started. This month I talked to Dr. Merlin Butler from Kansas University Medical Center about an interesting clinical case he described recently in the Journal of Pediatric Genetics, concerning cardiac presentations in a case of classic Ehlers-Danlos syndrome with COL5A1 mutations. Keep listening for that interview, but first, let's talk about the papers in this month's issue of the Journal. Our first paper, entitled "Effects of Genetic Variance Associated With Familial Hypercholesterolemia on LDL Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program." Comes from Yan Sun, Peter Wilson and co-authors on behalf of the V.A. Million Veterans Program. They were interested in the relatively between variants in LDLR, APOB and PCSK9, and LDL cholesterol in the general population. Low-frequency variants in these genes have been identified to underlie the greatly elevated LDL cholesterol seen in cases of familial hypercholesterolemia, but the effects of the population level are unknown. Using data from the Million Veterans Program, the team analyzed the associations between putatively pathogenic variants and the maximum recorded LDL cholesterol level, as measured repeatedly over a 15-year period, in over 330,000 participants. They restricted analysis to variants that were present in at least 30 people and found that eight of the 16 variants tested were associated with significantly higher LDL cholesterol. Through phenome-wide association analysis, they found that carriers had a higher likelihood of a diagnosis of hypercholesterolemia or coronary heart disease, but not of other diagnoses. Even though individuals carrying risk variants generally reduce their LDL cholesterol through statin treatment, they still had residual risk, suggesting that even earlier initiation of treatment may be required in individuals with genetic risk of high HDL. Continuing the theme, the next paper comes from Laurens Reeskamp, Merel Hartgers, Kees Hovingh and colleagues from the University of Amsterdam, and is entitled, "A Deep Intronic Variant in LDLR in Familial Hypercholesterolemia: Time to Widen the Scope?" This team had encountered a family with familial hypercholesterolemia, who did not carry a coding mutation in LDLR, APOB or PCSK9, and they wanted to figure out what was causing the elevated LDL cholesterol in this family. They conducted whole-genome sequencing in nine family members, five affected and four unaffected. They found a variant in an intron in LDLR, which resulted in an insertion of 97 nucleotides, leading to a frame shift in premature stop codon in exon 15 of LDLR. They confirmed the disease segregation in a second family, and found a frequency of over 0.2% in additional FH cases without a confirmed mutation. This study highlights the need to consider more than just exons when looking for causal variants, particularly in families where no coding mutations are identified. Next up, from Kathryn Siewert and Ben Voight from University of Pennsylvania, a paper reporting that "Bivariate Genome-Wide Association Scan Identified 6 Novel Loci Associated With Lipid Levels and Coronary Artery Disease." This paper started with a premise that, because heritable plasma lipids are genetically linked to coronary artery disease, we would have greater power to detect variants contributing to both traits by conducting joint GWAS analysis, rather than independent analyses for lipids or coronary disease, as has been done traditionally. Using data from over 500,000 individuals for CAD and over 180,000 individuals from the Global Lipid Genetics Consortium, they conducted a bivariate GWAS and identified six previously unreported loci that associated with CAD and either triglycerides, LDL cholesterol or total cholesterol. Many of these loci also had signals for effects on gene expression of genes in the region, suggesting that these novel loci may affect lipid levels and CAD risk through modulation of gene expression. Interestingly, for some of the newly-identified loci, there were multiple potential regulatory targets, suggesting that these loci may affect lipids and CAD through separate mechanisms. Overall, for closely-linked traits such as lipids and CAD, this joint GWAS approach gives additional power to detect novel variants. The next article comes from Terry Solomon, John-Bjarne Hansen and colleagues from University of California-San Diego and the Arctic University of Norway. Their paper concerns the "Identification of Common and Rare Genetic Variation Associated With Plasma Protein Levels Using Whole-Exome Sequencing and Mass Spectrometry." They were interested in identifying genetic variants that associate with plasma protein levels, both to understand genetic regulation and to identify potential sources of bias, where a genetic variant affects the assay used to quantify the protein, without necessarily altering biological components of the protein. Using data from 165 participants of the Tromsø Study, they quantified 664 proteins in plasma by tandem mass tag mass spectrometry and genotypes by whole-exome sequencing. They identified 109 proteins or peptides associated with genotype, and of these identified 49 that appeared to be technical artifacts based on genotype data. Of the rest, many of the genetic variants affected protein level by modulation of RNA, but some appeared to directly affect protein metabolism. Their method of quantifying multiple peptides from each protein and sequencing exons allowed them to identify spurious associations that would often be missed, and highlights the large number of artifacts that could be present in protein quantitative trait locus studies. At the same time, they show that over half of the pQTLs are real, with genetic variants affecting circulating proteins through diverse mechanisms. Our last of the full-length original research articles also applied proteomics. "Proteomic Analysis of the Myocardium in Hypertrophic Obstructive Cardiomyopathy" comes from Caroline Coats, Perry Elliott and coauthors from University College, London. They obtained myocardial samples from 11 patients with hypertrophic cardiomyopathy and measured over 1500 proteins using label-free proteomic analysis. They compared protein expression to six control samples from healthy hearts. They identified 151 proteins that were differentially expressed in HCM hearts, compared with control, and they validated a subset of these using an additional 65 myocardial samples from healthy and diseased subjects. Of eight validated differentially expressed proteins, they represented pathways in metabolism, muscle contraction, calcium regulation and oxidative stress. Of particular interest, they highlighted lumican as a novel disease protein, and showed the potential of proteomics to identify mechanisms underlying HCM. We have two research letters this month, the first from Hisato Suzuki, Kenjiro Kosaki and coauthors from Keio University School of Medicine at Tokyo. It's titled, "Genomic Comparison With Supercentenarians Identifies RNF213 as a Risk Gene for Pulmonary Arterial Hypertension." In this letter, they were interested in identifying genetic variants underlying pulmonary arterial hypertension. They hypothesized that individuals with extremely long lifespan would be less likely to carry potentially pathogenic variants. They performed whole-exome sequencing in 76 individuals with PAH and compared them to 79 supercentenarians who had lived for over 110 years. They report variants in RNF213 and TMEM8A that were present in PAH but not in the controls, suggesting these genes may be important in the pathophysiology of PAH. The second research letter comes from Tessa Barrett, Jeffrey Berger and colleagues from New York University School of Medicine, and is entitled, "Whole-Blood Transcriptome Profiling Identifies Women With Myocardial Infarction With Nonobstructive Coronary Artery Disease: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network." Most of the 750,000 acute MIs occurring in the U.S. each year are caused by obstructive coronary artery disease, but around 15% of the acute MIs occur in individuals whose arteries have less than 50% stenosis and are defined as unobstructed. These individuals are more likely to be female and of higher morbidity and mortality. In this AHSAFRM-funded project, the team sequenced whole-blood RNA from 32 women who presented with an MI with or without CAD, or controls. They report several thousand transcripts differing between groups on conducted pathway analysis, which highlighted several pathways, most notably estrogen signaling. This suggests that estrogen may be a novel component in MIs occurring in the absence of obstructive disease. We also have two clinical letters this month. The first, "Desmoplakin Variant-Associated Arrhythmogenic Cardiomyopathy Presenting as Acute Myocarditis," is brought to us by Kaitlyn Reichl, Chetan Shenoy and colleagues from University of Minnesota Medical School. They report a case of a 24-year-old man presenting with acute myocarditis, who was found to have a pathogenic variant in desmoplakin underlying arrhythmogenic cardiomyopathy, also present in his father and one brother. This case highlights myocarditis as a possible initial presentation of arrhythmogenic cardiomyopathy, which requires cardiac MRI and genetic testing for full evaluation. The second clinical letter comes from Judith Verhagen, Marja Wessels and co-authors from University Medical Center, Rotterdam, and is entitled, "Homozygous Truncating Variant in PKP2 Causes Hypoplastic Left Heart Syndrome." They report on a family with consanguineous parents, where two children were affected with left ventricular hypoplasia, leading to intrauterine death in one child and death at day 19 of life in a second child. Sequencing identified a variant in PKP2, which encodes plakophilin 2. Both parents were heterozygous for the mutation, and their affected children were homozygous for the mutation. This mutation resulted in disorganization of the sarcomere and affected localization of other proteins affecting gap junctions. The case highlights PKP2 variants as causal in hypoplastic left heart syndrome. Dr. Merlin Butler is a professor at Kansas University Medical Center and Director of their Division of Research and Genetics. Dr. Butler joined me to discuss an interesting case of Ehlers-Danlos Syndrome in a father and son, with heart failure in the father. This case is in press in the Journal of Pediatric Genetics, and the prepublication version is available online, published on the 13th of October 2018. We'll tweet out a link to that paper, if you're interested in viewing the full case, but here's Dr. Butler, who joined me to discuss it now. Dr. Butler: ... I'm a clinical geneticist here at University of Kansas Medical Center, and I see both adult and pediatric patients, but one of the more common reasons for referral to my adult side clinical genetic services is connective tissue disorders. And that's how we were involved with this particular family, a son and father, that led to my interest in looking at the question about genetics of cardiac transplantation of those patients that present for cardiology services because of heart failure and worked up and ultimately end up as a candidate for transplantation. And that transpired in this particular family, which the patient was a 13-year-old boy who was referred into the clinic because of connective tissue disorder. Actually the primary care wanted to rule out Ehlers-Danlos Syndrome. And so we evaluated the 13-year-old boy in the clinic setting, and then we ordered comprehensive connective tissue and next-generation DNA sequencing panel, and lo and behold, he had a mutation of the classical gene that causes classic Ehlers-Danlos, the collagen 5A1 gene. The gene variant was classified as unknown clinical significance, which is often the case as we know with this technology, next-generation sequencing. Regardless of the condition we're looking at, we find about 10% of time, the panel of tests, the panel of genes that come back that are tested. 10% of the time we find no variants, no spelling errors, no mutations. 10% of the time the results come back from the commercial laboratory ... these are clinic patients, so it's done in commercially-approved laboratories, clinically-approved laboratories ... and we find that about 10% is pathogenic, which means it's disease-causing. The gene variant or mutation has been reported before. There is information in the literature that we know that it causes disease, Ehlers-Danlos, whatever type. About 80% of the time, the results come back as unknown clinical significance, and this is related to connective tissue. You probably order a test in cardiology or any other service and you'll find the same area. Most of the variants come back as unknown. What is meant by that is they haven't been reported previously in the literature, and therefore we don't know ... They may be disease-causing, that particular change, but we don't know that. We as geneticists, we have to then figure out whether that gene variant is a mutation or background noise. So we go through a process by where we try to characterize that particular gene finding to see whether it could be causative in that particular patient we see, or if it looks like it's probably tolerated and is just background noise, and it has really probably no apparent phenotypic change resulting from that particular gene variant. So this particular gene variant that we found, the collagen 5A1, did meet the criteria. We looked for computer programs and silica prediction to see if it was tolerated or damaging. We looked at how common that gene variant is seen in the general population, looking at exact various types of genome databases at the laboratories used to search for that variant in the population that's been serviced by genetic services, to see how rare it is or how common it is. We also check to see if it's a missense change, missense variant that is, one amino acid got switched for a different amino acid. There are five classes of amino acids, so if they stay within the same class, that change one amino acid to the next probably doesn't have much meaning, but if it changes to an entirely different class, like positive to negative, hydrophilic to hydrophobic, that could make a big change at the protein translation level, and therefore impact on protein development and function. And then we looked to see if it's conserved in evolution. The laboratories that we use, they look at approximately 80 different animals, mammals, vertebrates, primates, non-mammal vertebrates, to see if that particular spelling change is conserved throughout evolution. If it is, if C is always that position 205 in the coding sequence of that gene throughout evolution, that means you need to have C at that position, not A, G or T, because that would be conserved and impact that we don't want to change that, because it's conserved through evolution. So those kind of criteria, how common it is in the population, how conserved it is, what the amino acid change might be and what the computer programs predict that change might relate to the function of the protein. So we used those criteria, found this gene variant, although it hadn't been reported before ... well, it hasn't been characterized as pathogenic. In this particular family, 13-year-old son and 55-year-old father, they both had the classical features of classic Ehlers-Danlos, so that gene variant, we know at this point is informative. Dr. Ferguson: That's a really helpful introduction to how you go about looking at variants and screening them and picking the ones of most importance. So you had this 13-year-old patient who came in and then you tested the patient, and then did you also test both parents? Other family members? Dr. Butler: Well, the mother was no longer in the loop, so the primary care, the pediatrician, referred this 13-year-old boy because of joint laxity. He had experienced multiple spontaneous knee dislocations, beginning around nine years of age. He was 13 when I saw him in clinic. He had a history of knee pain, generalized joint hypermobility, loose skin, excessive bruising and poor scarring. And he had that history coming in, and we certainly could identify those findings on this patient. In fact, we reported this patient in the literature. The title of the paper is "Classic Ehlers-Danlos Syndrome in a Son and Father with a Heart Transplant Performed in the Father," published in Journal of Pediatric Genetics, but during a genetics clinic visit, we assessed a hypermobility Beighton scale, that we used to determine the degree of hypermobility, hyperflexibility, and we recorded a score of eight out of nine. Nine is the maximum number. And what we use as kind of a cut-off, this score is five or more, five out of nine or more, then that would indicate that probably there is some kind of joint issues, connective tissue disorder in the way. He had no heart murmur detected, normal rate and rhythm, but a previous echocardiogram showing he had no valvular problems but he had aortic root dilation. He also had skin marbling, atrophic scars, particularly on the lower leg, and increased pigment secondary to easy bruising. He had asymmetry of the anterior body wall, pretty classical findings that we recognize in Ehlers-Danlos. Dr. Ferguson: So the reason we're talking to you about this is actually less related to the son, right? And then related to what you found in the father. Dr. Butler: The father, right. So the father was 55 years old when we saw him. So we did testing on the son, based on his examinations, and then we obtained DNA and we found out, had the sequencing. We found he had a gene variant of the collagen 5A1 gene. And the collagen 5A1 codes for collagen, low fibrils protein changes, and that's a classical finding we see in Ehlers-Danlos. So we then, on follow-up, we looked more closely at the father, based on what we found in the child, and the father is 55 years of age and he exhibited similar clinical features seen in his son, including stretchable, thin skin, poor scarring, hypermobile joints, with pain and easy bruising. He had a Beighton score of six out of nine, but due to multiple knee surgeries, we were really not able to able to assess his knee findings. And he had strabismus repair when he was like 12 years of age. He had surgery on his right knee due to frequent dislocations, and had bilateral foot surgeries due to flat feet, pes planus. He had a stroke at 37 years of age, but without hypertension. At 43 years of age he underwent a heart transplant because of heart failure with no known cause, such as infections or anatomical defects or metabolic problems seen. And at 54 years of age he had fusion of the lower vertebrae, correct complications, nerve compression, impacting ambulation. So he had multiple, multiple problems, and we did DNA testing on him. He also had the same gene variant of the collagen 5A1 gene, which causes classic Ehlers-Danlos Syndrome. Dr. Ferguson: Yeah, so he essentially had been undiagnosed his entire life, I guess. Dr. Butler: In his entire life, he just kind of lived with it. Obviously no one really picked it up because he had multiple, multiple orthopedic surgeries. Of course he had the cardiac transplant because of a very large heart size. They didn't really find out what had taken place with that. They didn't find any reason why he had heart failure. So, because of this connective tissue issue, I began to think more closely about this. Could somehow his cardiac transplantation due to no determined reason why he had heart failure, could that somehow be related to a connective tissue problem, such as classic Ehlers-Danlos? And classic Ehlers-Danlos is fairly common, about one in 20,000 people. As far as our concern in the field of genetics, one in 20,000 is common, because we see rare diseases. So one in 20,000 is common. There's like six different categories of Ehlers-Danlos in classic and hypermobile form, vascular form, but he had the clinical findings, he and his son, and he had mutation of a gene that causes classic Ehlers-Danlos. So the thrust of this communication is, could it be that there may be a group of individuals that are on a heart transplantation service, waiting to be transplanted, that might have a connective tissue disorder, such as Ehlers-Danlos or one of the other connective tissue disorders, that could be an issue and a causation of their cardiac issues? We know that there are around 70 genes being recognized that cause connective tissue, and these numbers increase all the time as we learn more about genetics and the capabilities of testing. There are over 130 recognized genes that are thought to play a role in hereditary cardiomyopathies and there are now thought to be over 230 genes that are commercially available in a comprehensive cardiovascular next-generation DNA panels, and several of those genes are collagen genes. So we know there are hundreds of genes that play a role with cardiac health, I guess. Disturbance of those genes, several of those could be connective tissue. Obviously there's others involved, too ... myopathies and conduction issues. But the question I would have, the focus is, could there be a group that would have a connective tissue? And why is that important? Well, not only do they have issues when it comes to these multiple surgical concerns, but they may have, obviously, concerns that might be related to complications of surgery. We know that connective tissue disorders, they have poor wound healing, scarring and other tissue involvement such as vascular anomalies, aneurysms. So they become ... whether it's for cardiac procedures or whether it's orthopedic, whatever ... they become poor candidates for surgical intervention, for surgical operation procedures, because of the complications of surgery. Connective tissue, poor wound healing, scarring. And because connective tissue is involved in not only the skin, but involves internal organs such as the vessels, where you're concerned about aneurysms and vascular anomalies, that could be playing a role. So there may be more complications related to the surgical procedures than your typical patient who undergoes heart transplantation. So I think that would be important to know, so I would encourage, for the cardiology services, for patients that are on these transplant care and services, to consider a comprehensive genetic DNA analysis to look at connective tissues, as well as other causations of cardiac disease. As I mentioned, there's over 200 different genes been recognized now on comprehensive DNA testing panels related to cardiac and connective tissue problems. So, I would encourage that patients that are on the transplant list, they should undergo a next-generation detailed comprehensive connective and cardiovascular panel ... they're certainly available in several laboratory settings ... that might help lead to not only the diagnosis of the cardiac issues, but might help in medical management and monitoring and the surveillance, as well as the surgical interventions and care following the surgical procedures might be taking place. Frequently have an arterial wall might be a little fragile and obviously clamping during surgical procedures for an extended period of time might cause some trauma, even to a normal artery, let alone an artery that might be disorganized because of connective tissue problem. Dr. Ferguson: Yeah. Dr. Butler: So those complications might occur as well, too, during the procedure or following the procedure. Even there may not be any aneurysms going in, there might be a weakness of the arterial wall at the clamp site that could lead to an aneurysm following the procedure, so it needs to be monitored. So I'm just bringing these to the medical attention that may or may not be out there, but I want to bring this to ... You know, there have been over 90,000 heart transplants been done since 1983, at least that many, and there's 23 million people worldwide that are affected with congestive heart failure, and that's about 7.5 million people in North America. Dr. Ferguson: Yeah. Dr. Butler: So it's out there. Some of these genetic conditions are rare, but collectively they're common. Ehlers-Danlos, one in 20,000, is probably considered rare, but yet it still is not rare to the person that has it. Dr. Ferguson: Right, right, and maybe enriched in these patient populations. So is this something you think that could be sort of found with more careful physical exams, or do you think that [crosstalk] genomic sequencing is sort of the best way to get at this? Dr. Butler: Well, I think that Beighton scale we just mentioned, the hypermobility scale, just to see if there's, you know, if it's pretty common. Most adults can't put their palms on the floor when they're standing up. Dr. Ferguson: I certainly can't. Dr. Butler: That is usually not gonna happen for multiple reasons. But maybe some of the cardiologists are, but those that aren't, maybe they should consider, just check for hyperflexibility in their adult patient. [crosstalk] Dr. Ferguson: Yeah, that seems like an easy [crosstalk] click-and-check, right? Dr. Butler: Right. There being loose skins, poor scarring. You can ask the patient, obviously. Easy bruisability and poor scars, and it's pretty obvious in these conditions. I mean, on a physical exam it jumps out at you, particularly the multiple scars and bruising on the lower extremities with the pigmented because of iron deposits. You'll see that pretty clear in the scarring issues. And they'll tell you, too. I mean, the patients, they know. "Oh, yeah. I'm very hyperflexible." So you just ask the question and the patients will tell you. They say yes, and then it might need further testing physically; that is, actually do the exam and see if they have, on this Beighton scale, what the hyperflexibility score looks like. And if it is positive ... what we consider positive is five and above, five out of nine ... then those would candidates for a comprehensive DNA testing, whether it's related to cardiomyopathies, but I think connective tissue collection genes. Like I say, there's roughly 70 of these genes out there now that we test for in the commercial clinical laboratory setting. That should be monitored, as well as adding other genes if need be. So I'd encourage that. Physical examination number one. If it's positive, then check into a DNA panel for these types of disorders. It could help long-term for the care and outcome of the patient. Dr. Ferguson: Yeah. I do think that's really important from the patient perspective and then, if more of these cases start being reported, I think it's very interesting also from the research perspective to find out what are the mechanisms that are potentially linking these mutations to cardiac disorders which have- [crosstalk] Dr. Butler: That's true, and also realize that a lot of these patients have hypotension, and that can lead to some complications before, during and after surgical intervention, too. Dr. Ferguson: Yeah. Dr. Butler: So that's important to realize. Dr. Ferguson: Very important. Yeah. So thank you for telling us about this interesting case and for raising this. I think it's an important issue and I'm sure a lot of the cardiologists and clinicians listening will start to look out for connective tissue disorders in their own patients. Dr. Butler: I think, first thing is just ask questions. Are you hyperflexible? And they'll tell you. It's something that is very obvious to the patient. It will be obvious to the physician once he or she puts their hands on the patient, examine the patient, they realize, "Oh, this patient really is quite hyperflexible, digits and arms and knees and elbows," et cetera, et cetera. But, just ask the question, are they hyperflexible? If they say no, then the connective tissue is lower. It still could be. There could still be some aneurysms, those kind of things going on because there's, like I say, there's 70 genes, and there's six types of Ehlers-Danlos, so there's many other conditions out there that kind of look like an Ehlers-Danlos, but they're not. They may have another gene involving protein that's related to connective tissue, but not in the Ehlers-Danlos group of disorders or genes. Still could play a role. Could be similar. They may [inaudible] aneurysms, and that's important to know before they get into the procedures, too. Dr. Ferguson: Yeah, really important, really interesting. Thank you so much for joining us. Thanks, everyone, for listening. And I wish you all the best for the holiday season, and a very happy new year. We're looking forward to bringing you lots more in 2019. This podcast was brought to you by Circulation: Genomic and Precision Medicine , and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association, 2018.…

Getting Personal: Omics of the Heart

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24 January 2019 13:03

6 years тому13:03

13:03

Jane Ferguson: Hello everyone, and happy new year. Welcome to episode 24 of Getting Personal: Omics of the Heart. It's January 2019, I am Jane Ferguson, an assistant professor at Vanderbilt University Medical Center and an associate editor at Circulation Genomic and Precision Medicine . We have a great line-up of papers this month in the journal, so let's jump right into the articles. First up, a paper from Christopher Nelson, Nilesh Samani, and colleagues from the University of Lester entitled, "Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 Inhibitors." I think most listeners are well aware of the efficacy of PCSK9 inhibition in reducing cardiovascular risk. However, as a relatively new treatment option, we do not yet have data on potential long-term side effects of PCSK9 inhibition. In this study, they utilized genetics as a proxy to understand potential long-term consequences of lower PCSK9 activity. They examined a PCSK9 variant that associates with lower LDL, as well as examining two LDL-lowering variants in HMGCR, the target of statins, which served as a positive control of sorts. They used data from over 479,000 individuals in the UK Biobank and looked for associations between the three LDL-lowering variants and 80 different phenotypes. For the PCSK9 variant, the allele which is associated with lower LDL was significantly associated with the higher risk of type 2 diabetes, higher BMI, higher waist circumference, higher waist-hip ratio, higher diastolic blood pressure, as well as increased risk of type 2 diabetes and insulin use. The HMGCR variants were similarly associated with type 2 diabetes as expected. Mediation analysis suggested that the effect of the PCSK9 variant on type 2 diabetes is independent of its effect on obesity. There were nominal associations between the PCSK9 variant and other diseases, including depression, asthma, chronic kidney disease, venous thromboembolism, and peptic ulcer. While genetics cannot fully recapitulate the information that would be gained from long-term clinical follow up, these data suggest that like statins, PCSK9 inhibition may increase the risk of diabetes and potentially other disease. Overall, the cardiovascular efficacy of PCSK9 inhibition may outweigh these other risks, however, future studies should carefully examine these potential side effects. Next up, we have a paper from Xiao Cui, Fang Qin, Xinping Tian, Jun Cai, and colleagues from Peking Uni and Medical College, on "Novel Biomarkers for the Precise Diagnoses and Activity Classification of Takayasu's Arteritis." They were interested in identifying protein biomarkers of Takayasu arteritis, to improve diagnosis and understanding of disease activity in this chronic vascular disease. They ran a proteomic panel including 440 cytokines on 90 individuals, including individuals with active disease, inactive disease, and healthy controls. They found a number of candidates and validated one protein, TIMP-1, as a specific diagnostic biomarker for Takayasu arteritis. For assessing disease activity, there was no single biomarker that could be used for classification, however, the combination of eight different cytokines identified through random forest-based recursive feature elimination and [inaudible] regression, including CA 125, FLRG, IGFBP-2, CA15-3, GROa, LYVE-1, ULBP-2, and CD 99, were able to accurately discriminate disease activity versus inactivity. Overall, this study was able to identify novel biomarkers that could be used for improved diagnosis and assessment of Takayasu arteritis, and may give some clues as to the mechanisms of pathogenesis. Our next paper is entitled, "Familial Sinus Node Disease Caused By Gain of GIRK Channel Function," and comes from Johanna Kuß, Birgit Stallmeyer, Marie-Cécile Kienitz, and Eric Schulze-Bahr, from University Hospital Münster. They were interested in understanding novel genetic underpinnings of inherited sinus node dysfunction. A recent study identified a gain of function mutation in GNB2 associated with sinus node disease. This mutation led to enhanced activation of the G-protein activated inwardly rectifying potassium channel, or GIRK, prompting the researchers to focus their interest on the genes encoding the GIRK subunits, KCNJ3 and KCNJ5. They sequenced both genes in 52 patients with idiopathic sinus node disease, and then carried out whole exome sequencing in family members of patients with potential disease variants in either gene. They identified a non-synonymous variant in KCNJ5, which was not present in the EVS or ExAC databases, and which segregated with disease in the affected family. This variant was associated with increased GIRK currents in a cell system, and in silico models, predicted the variant altered or spermine binding site within the GIRK channel. Thus, this study demonstrated that a gain of function mutation in a GIRK channel subunit associates with sinus node disease, and suggests that modulation of GIRK channels may be a viable therapeutic target for cardiac pacemaking. Our next paper, "Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy," comes from Emma Singer, Richard Bagnall, and colleagues from the Centenary Institute and the University of Sydney. They wanted to understand the impact of variants in MYBCP3, a known hypertrophic cardiomyopathy gene, on splicing. They recruited individuals with a clinical diagnosis of hypertrophic cardiomyopathy and genetic testing of cardiomyopathy-related genes. They further examined individuals with a variant in MYBCP3 which had an in silico prediction to affect splicing. They sequenced RNA from blood or from fixed myocardial tissue and assessed the relationship between each DNA variant and gene splicing variation. Of 557 subjects, 10% carried rare splice site variants. Of 29 potential variants identified, they examined 9 which were predicted to affect splicing, and found that 7 of these were indeed associated with splicing errors. Going back to the families, they were able to reclassify four variants in four families from uncertain clinical significance to likely pathogenic, demonstrating the utility of using RNA analysis to understand pathogenicity in genetic testing. The next paper this issue comes from Catriona Syme, Jean Shin, Zdenka Pausova, and colleagues from the University of Toronto, and is entitled, "Epigenetic Loci of Blood Pressure: Underlying Hemodynamics in Adolescents and Adults." A recent large meta epigenome-wide association study identified methylation loci that associate with blood pressure. In this study, they wanted to understand more about how these loci related to blood pressure and hemodynamics. They recruited adolescents and middle-aged adults and assessed 13 CPG loci for associations with hemodynamic markers, including systolic and diastolic blood pressure, heart rate, stroke volume, and total peripheral resistance, measured over almost an hour during normal activities. Several of the loci replicated associations with blood pressure, and two of these also showed age-specific associations with hemodynamic variables. One site in PHGDH was particularly associated with blood pressure and stroke volume in adolescents, as well as with body weight and BMI, where lower methylation resulting in higher gene expression associated with higher blood pressure. A second site in SLC7A11 associated with blood pressure in adults but not adolescents, with lower methylation and consequent higher gene expression associated with increased blood pressure. Overall, this study indicates that methylation mediated changes in gene expression may modulate blood pressure and hemodynamic responses in an age-dependent manner. Next up is a research letter from Ben Brumpton, Cristen Willer, George Davey Smith, Bjørn Olav Åsvold, and colleagues from the Norwegian University of Science and Technology, entitled, "Variation in Serum PCSK9, Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 Inhibition: A GWAS and Mendelian Randomization Study in the Nord-Trøndelag Health Study, Norway." As we heard about from the first study this issue, the long-term side effects of PCSK9 inhibition remain unknown. In this study, they also applied a genetic approach to understand potential unanticipated consequences of PCSK9 inhibition. They analyzed phenotypes from over 69,000 participants in the Nord-Trøndelag Health Study and measured serum PCSK9 in a subset. In PCSK9 GWAS of over 3,600 people, with replication in over 5,000 individuals from the twin gene study. They defined a genetic risk score for serum PCSK9 and assessed the relationship between genetically predicted PCSK9 and outcomes. They saw the expected associations between lower PCSK9 and lower LDL and coronary heart disease risk. However, there was minimal evidence for associations with other outcomes. While our first study in this issue, from Nelson, et al, found that lower PCSK9 from a single genetic variant was associated with higher diabetes risk, this risk was not found here using the genetic risk score. Differences in the genetic definitions and in the populations used can perhaps explain these differences between the two studies, but overall, the studies are consistent in suggesting that long-term PCSK9 inhibition is unlikely to be associated with major adverse outcomes. Our second research letter comes from Young-Chang Kwon, Bo Kyung Sim, Jong-Keuk Lee, and colleagues from Asan Medical Center in Seoul, on behalf of the Korean Kawasaki Disease Genetics Consortium. The title is, "HLA-B54:01 is Associated with Susceptibility to Kawasaki Disease," and reports on novel Kawasaki disease variants. HLA genes have been previously associated with disease, and in this report, the authors sequenced selected axons in HLA-DRB1, HLA-DQB1, HLA-A, HLA-B, HLA-C, and HLA-DBP1 in 160 Kawasaki disease patients and 278 controls. They find a significant association with HLA-B, and replicated this in a sample of 618 Kawasaki disease patients, compared with over 14,000 in-house controls. They identified specific amino acid residues conferring disease susceptibility, highlighting HLA-B as a potential modulator of Kawasaki disease. Our third and final research letter concerns "Serum Magnesium and Calcium Levels and Risk of Atrial Fibrillation: a Mendelian Randomization Study," and comes to us from Susanna Larsson, Nikola Drca, and Karl Michaëlsson, from the Karolinska Institute. Because magnesium and calcium are known to influence atrial fibrillation, this group was interested in whether genetic predictors of serum methyls associated with disease. They constructed genetic predictors from GWAS of calcium in over 61,000 individuals, and GWAS of magnesium in over 23,000 individuals. They applied these predictors to an AF GWAS including over 65,000 cases and over 522,000 controls. Genetically predicted magnesium was inversely associated with atrial fibrillation, while there was no association with genetically predicted calcium. While this study does not definitively prove causality, future studies aimed at assessing whether dietary or other strategies to raise serum magnesium are protective against AF may yield novel strategies for disease prevention. And that's it from us for this month. Thank you for listening, and come back next month for more from Circulation Genomic and Precision Medicine. This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association, 2019.…

Getting Personal: Omics of the Heart

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Episode 22 Nov 2018 12:34

6 years тому12:34