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Interactions Between Enhanced Polygenic Risk Scores and Lifestyle for Cardiovascular Disease, Diabetes, and Lipid Levels Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-01-12 Yixuan Ye; Xi Chen; James Han; Wei Jiang; Pradeep Natarajan; Hongyu Zhao
Background:Both lifestyle and genetic factors confer risk for cardiovascular diseases, type 2 diabetes, and dyslipidemia. However, the interactions between these 2 groups of risk factors were not comprehensively understood due to previous poor estimation of genetic risk. Here we set out to develop enhanced polygenic risk scores (PRS) and systematically investigate multiplicative and additive interactions
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Genetic Association Between Hypoplastic Left Heart Syndrome and Cardiomyopathies Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-16 Jeanne L. Theis; Jessie J. Hu; Rhianna S. Sundsbak; Jared M. Evans; William R. Bamlet; M. Yasir Qureshi; Patrick W. O’Leary; Timothy M. Olson
Background:Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to MYH6 variants, implicating overlap in genetic etiologies of structural and myopathic heart disease.Methods:Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband
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Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-14 Eythor Bjornsson; Kristbjorg Gunnarsdottir; Gisli H. Halldorsson; Asgeir Sigurdsson; Gudny A. Arnadottir; Hakon Jonsson; Eva F. Olafsdottir; Sebastian Niehus; Birte Kehr; Gardar Sveinbjörnsson; Steinunn Gudmundsdottir; Anna Helgadottir; Karl Andersen; Gudmar Thorleifsson; Gudmundur I. Eyjolfsson; Isleifur Olafsson; Olof Sigurdardottir; Jona Saemundsdottir; Ingileif Jonsdottir; Olafur Th. Magnusson;
Background:Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels.Methods:We analyzed
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Bayesian Inference Associates Rare KDR Variants With Specific Phenotypes in Pulmonary Arterial Hypertension Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-15 Emilia M. Swietlik; Daniel Greene; Na Zhu; Karyn Megy; Marcella Cogliano; Smitha Rajaram; Divya Pandya; Tobias Tilly; Katie A. Lutz; Carrie C.L. Welch; Michael W. Pauciulo; Laura Southgate; Jennifer M. Martin; Carmen M. Treacy; Christopher J. Penkett; Jonathan C. Stephens; Harm J. Bogaard; Colin Church; Gerry Coghlan; Anna W. Coleman; Robin Condliffe; Christina A. Eichstaedt; Mélanie Eyries; Henning
Background:Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.Methods:We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were
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Epigenomic Profiles of African-American Transthyretin Val122Ile Carriers Reveals Putatively Dysregulated Amyloid Mechanisms Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-01-11 Gita A. Pathak; Frank R. Wendt; Antonella De Lillo; Yaira Z. Nunez; Aranyak Goswami; Flavio De Angelis; Maria Fuciarelli; Henry R. Kranzler; Joel Gelernter; Renato Polimanti
Background:The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty
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Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-01-12 Nicholas A. Marston; Giorgio E.M. Melloni; Yared Gurmu; Marc P. Bonaca; Frederick K. Kamanu; Carolina Roselli; Christina Lee; Ilaria Cavallari; Robert P. Giugliano; Benjamin M. Scirica; Deepak L. Bhatt; Philippe Gabriel Steg; Marc Cohen; Robert F. Storey; Anthony C. Keech; Itamar Raz; Ofri Mosenzon; Eugene Braunwald; Steven A. Lubitz; Patrick T. Ellinor; Marc S. Sabatine; Christian T. Ruff
Background:Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease.Methods:We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated
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Polygenic Risk Score for Low-Density Lipoprotein Cholesterol Is Associated With Risk of Ischemic Heart Disease and Enriches for Individuals With Familial Hypercholesterolemia Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-01-13 Haoyu Wu; Vincenzo Forgetta; Sirui Zhou; Sahir R. Bhatnagar; Guillaume Paré; J. Brent Richards
Background:The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH).Methods:We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its
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Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-01-15 Ekanem N. Ekure; Adebowale Adeyemo; Hanhan Liu; Ogochukwu Sokunbi; Nnenna Kalu; Ariel F. Martinez; Babajide Owosela; Cedrik Tekendo-Ngongang; Yonit A. Addissie; Akinsanya Olusegun-Joseph; Desmond Ikebudu; Seth I. Berger; Maximilian Muenke; Zhe Han; Paul Kruszka
Background:Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease.Methods:Ninety-eight participants with CHD and an average age
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Sexual Differences in Genetic Predisposition of Coronary Artery Disease Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-17 Yunfeng Huang; Qin Hui; Marta Gwinn; Yi-Juan Hu; Arshed A. Quyyumi; Viola Vaccarino; Yan V. Sun
Background:The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score (GRS) of CAD.Methods:Using data from the UK Biobank, we constructed a CAD-GRS based on all known loci, 3 mediating trait-based (blood pressure, lipids, and body
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Developing and Optimizing Innovative Tools to Address Familial Hypercholesterolemia Underdiagnosis Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-01-22 Gemme Campbell-Salome; Laney K. Jones; Max F. Masnick; Nephi A. Walton; Catherine D. Ahmed; Adam H. Buchanan; Andrew Brangan; Edward D. Esplin; David G. Kann; Ilene G. Ladd; Melissa A. Kelly; Iris Kindt; H. Lester Kirchner; Mary P. McGowan; Megan N. McMinn; Ana Morales; Kelly D. Myers; Matthew T. Oetjens; Alanna Kulchak Rahm; Tara J. Schmidlen; Amanda Sheldon; Emilie Simmons; Moran Snir; Natasha T
Background:Familial hypercholesterolemia (FH) is the most common cardiovascular genetic disorder and, if left untreated, is associated with increased risk of premature atherosclerotic cardiovascular disease, the leading cause of preventable death in the United States. Although FH is common, fatal, and treatable, it is underdiagnosed and undertreated due to a lack of systematic methods to identify individuals
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Promise and Peril of Population Genomics for the Development of Genome-First Approaches in Mendelian Cardiovascular Disease Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-02-01 Victoria N. Parikh
The rich tradition of cardiovascular genomics has placed the field in prime position to extend our knowledge toward a genome-first approach to diagnosis and therapy. Population-scale genomic data has enabled exponential improvements in our ability to adjudicate variant pathogenicity based on allele rarity, and there has been a significant effort to employ these sizeable data in the investigation of
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Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-02-10 Alice Ghidoni; Perry M. Elliott; Petros Syrris; Hugh Calkins; Cynthia A. James; Daniel P. Judge; Brittney Murray; Julien Barc; Vincent Probst; Jean-Jacques Schott; Jiang-Ping Song; Richard N.W. Hauer; Edgar T. Hoorntje; J. Peter van Tintelen; Eric Schulze-Bahr; Robert M. Hamilton; Kirti Mittal; Christopher Semsarian; Elijah R. Behr; Michael J. Ackerman; Cristina Basso; Gianfranco Parati; Davide Gentilini;
Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants,
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Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2021-02-09 Marie-Pierre Dubé; Marc-André Legault; Audrey Lemaçon; Louis-Philippe Lemieux Perreault; René Fouodjio; David D. Waters; Simon Kouz; Fausto J. Pinto; Aldo P. Maggioni; Rafael Diaz; Colin Berry; Wolfgang Koenig; Jose Lopez-Sendon; Habib Gamra; Ghassan S. Kiwan; Géraldine Asselin; Sylvie Provost; Amina Barhdadi; Maxine Sun; Mariève Cossette; Lucie Blondeau; Ian Mongrain; Anick Dubois; David Rhainds;
Background - The randomized, placebo-controlled COLchicine Cardiovascular Outcomes Trial (COLCOT) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post-hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine
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Associations Between Alcohol Intake and Genetic Predisposition With Atrial Fibrillation Risk in a National Biobank Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-06 Jennifer L. Halford; Lu-Chen Weng; Seung Hoan Choi; Sean J. Jurgens; Valerie N. Morrill; Shaan Khurshid; Ludovic Trinquart; Emelia J. Benjamin; Patrick T. Ellinor; Steven A. Lubitz
Background:Excess alcohol intake and inherited predisposition may increase risk of atrial fibrillation (AF). We assessed the association between alcohol intake, polygenic predisposition to AF, and incident AF in the UK Biobank, a prospective cohort study.Methods:In 376 776 UK Biobank participants enrolled between 2006 and 2010, we tested alcohol consumption (stratified by the Centers of Disease Control
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Population Bias in Polygenic Risk Prediction Models for Coronary Artery Disease Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-10 Damian Gola; Jeanette Erdmann; Kristi Läll; Reedik Mägi; Bertram Müller-Myhsok; Heribert Schunkert; Inke R. König
Background:Individual risk prediction based on genome-wide polygenic risk scores (PRSs) using millions of genetic variants has attracted much attention. It is under debate whether PRS models can be applied—without loss of precision—to populations of similar ethnic but different geographic background than the one the scores were trained on. Here, we examine how PRS trained in population-specific but
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KCNQ1 and Long QT Syndrome in 1/45 Amish Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-03 Elizabeth A. Streeten; Vincent Y. See; Linda B.J. Jeng; Kristin A. Maloney; Megan Lynch; Andrew M. Glazer; Tao Yang; Dan Roden; Toni I. Pollin; Melanie Daue; Kathleen A. Ryan; Cristopher Van Hout; Nehal Gosalia; Claudia Gonzaga-Jauregui; Aris Economides; James A. Perry; Jeffrey O’Connell; Amber Beitelshees; Kathleen Palmer; Braxton D. Mitchell; Alan R Shuldiner; Regeneron Genetics Center*
Background:In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health.Methods:Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification
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Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-06 Amelia Weber Hall; Mark Chaffin; Carolina Roselli; Honghuang Lin; Steven A. Lubitz; Valerio Bianchi; Geert Geeven; Kenneth Bedi; Kenneth B. Margulies; Wouter de Laat; Nathan R. Tucker; Patrick T. Ellinor
Background:Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes
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SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-09 Yanushi D. Wijeyeratne; Michael W. Tanck; Yuka Mizusawa; Velislav Batchvarov; Julien Barc; Lia Crotti; J. Martijn Bos; David J. Tester; Alison Muir; Christian Veltmann; Seiko Ohno; Stephen P. Page; Joseph Galvin; Rafik Tadros; Martina Muggenthaler; Hariharan Raju; Isabelle Denjoy; Jean-Jacques Schott; Jean-Baptiste Gourraud; Doris Skoric-Milosavljevic; Eline A. Nannenberg; Richard Redon; Michael Papadakis;
Background:Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A
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Cardiac Imaging of Aortic Valve Area From 34 287 UK Biobank Participants Reveals Novel Genetic Associations and Shared Genetic Comorbidity With Multiple Disease Phenotypes Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-10-30 Aldo Córdova-Palomera; Catherine Tcheandjieu; Jason A. Fries; Paroma Varma; Vincent S. Chen; Madalina Fiterau; Ke Xiao; Heliodoro Tejeda; Bernard D. Keavney; Heather J. Cordell; Yosuke Tanigawa; Guhan Venkataraman; Manuel A. Rivas; Christopher Ré; Euan Ashley; James R. Priest
Background:The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases.Methods:From a sample of 34 287 white British ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac magnetic resonance imaging sequences of the aortic valve. Aortic valve area measurements were submitted to genome-wide
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Metabolomic Effects of Hormone Therapy and Associations With Coronary Heart Disease Among Postmenopausal Women Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-03 Raji Balasubramanian; Olga Demler; Marta Guasch-Ferré; Nina P. Paynter; Ryan Sheehan; Simin Liu; JoAnn E. Manson; Jordi Salas-Salvadó; Miguel Á. Martínez-Gonzalez; Frank B. Hu; Clary Clish; Kathryn M. Rexrode
Background:In the WHI-HT trials (Women’s Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not.Methods:Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the
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Spontaneous Coronary Artery Dissection Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-10-30 Keren J. Carss; Anna A. Baranowska; Javier Armisen; Tom R. Webb; Stephen E. Hamby; Diluka Premawardhana; Abtehale Al-Hussaini; Alice Wood; Quanli Wang; Sri V. V. Deevi; Dimitrios Vitsios; Samuel H. Lewis; Deevia Kotecha; Nabila Bouatia-Naji; Stephanie Hesselson; Siiri E. Iismaa; Ingrid Tarr; Lucy McGrath-Cadell; David W. Muller; Sally L. Dunwoodie; Diane Fatkin; Robert M. Graham; Eleni Giannoulatou;
Background:Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture
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Clinical Profile of Cardiac Involvement in Danon Disease Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-05 Dor Lotan; Joel Salazar-Mendiguchía; Jens Mogensen; Faizan Rathore; Aris Anastasakis; Juan Kaski; Pablo Garcia-Pavia; Iacopo Olivotto; Philippe Charron; Elena Biagini; Anwar Baban; Giuseppe Limongelli; Waddah Ashram; Yishay Wasserstrum; Joseph Galvin; Esther Zorio; Attilio Iacovoni; Lorenzo Monserrat; Paolo Spirito; Maria Iascone; Michael Arad
Background:The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe.Methods:Clinical and genetic data were collected in 16 cardiology centers from 8 European countries.Results:The
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Comprehensive Investigation of Circulating Biomarkers and Their Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-10-30 Daniela Zanetti; Stefan Gustafsson; Themistocles L. Assimes; Erik Ingelsson
Background:Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood.Methods:We performed multivariable-adjusted regressions and 2-sample Mendelian randomization analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451 933 participants
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Monoallelic Mutations in CC2D1A Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-16 Alvin Chun Hang Ma; Christopher Chun Yu Mak; Kit San Yeung; Steven Lim Cho Pei; Dingge Ying; Mullin Ho Chung Yu; Kazi Md Mahmudul Hasan; Xiangke Chen; Pak Cheong Chow; Yiu Fai Cheung; Brian Hon Yin Chung
Background:Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous.Methods:We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like
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Systematic Evaluation of KCNQ1 variant using ACMG/AMP Guidelines and Risk Stratification in Long QT Syndrome Type 1: Expression of Concern Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-15
The article “Systematic Evaluation of KCNQ1 variant using ACMG/AMP Guidelines and Risk Stratification in Long QT Syndrome Type 1” by Kashiwa et al, which published on September 16, 2020 in the journal (Circulation: Genomic and Precision Medicine. https://doi.org/10.1161/CIRCGEN.120.002926) enrolled a total of 927 long-QT syndrome type 1 (LQT1) patients from two LQT registries. However, substantial
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Life by the Numbers Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-08 Casey Mulligan Walsh
When I worked as a speech-language pathologist, there was always a bright spot just after the start of the school year: my birthday. One morning several years ago, the secretary announced with a flourish: “…and a very happy birthday to Mrs. Walsh and to Coach Perkins, who’s…30 today!” Hmmph. Though I was happy to share, I also detected a ridiculous twinge of disappointment. But I’m 60 today! When I
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Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-12-07 Neal K. Lakdawala; Iacopo Olivotto; Sharlene M. Day; Larry Han; Euan A. Ashley; Michelle Michels; Jodie Ingles; Christopher Semsarian; Daniel Jacoby; John L. Jefferies; Steven D. Colan; Alexandre C. Pereira; Joseph W. Rossano; Sam Wittekind; James S. Ware; Sara Saberi; Adam S. Helms; Allison L. Cirino; Leslie A. Leinwand; Christine E. Seidman; Carolyn Y. Ho
Background:The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts.Methods:Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed.Results:Of 5873 patients (3788 genotyped), 2226 (37
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Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-24 Sarah Costa; Argelia Medeiros-Domingo; Alessio Gasperetti; Deniz Akdis; Wolfgang Berger; Cynthia A. James; Frank Ruschitzka; Corinna B. Brunckhorst; Firat Duru; Ardan M. Saguner
Background:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC
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Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-11-23 Patrick S. Connell; Amy M. Berkman; BriAnna M. Souder; Elisa J. Pirozzi; Julia J. Lovin; Jill A. Rosenfeld; Pengfei Liu; Hari Tunuguntla; Hugh D. Allen; Susan W. Denfield; Jeffrey J. Kim; Andrew P. Landstrom
Background:TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population
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Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-21 Lu-Chen Weng,Amelia Weber Hall,Seung Hoan Choi,Sean J Jurgens,Jeffrey Haessler,Nathan A Bihlmeyer,Niels Grarup,Honghuang Lin,Alexander Teumer,Ruifang Li-Gao,Jie Yao,Xiuqing Guo,Jennifer A Brody,Martina Müller-Nurasyid,Katharina Schramm,Niek Verweij,Marten E van den Berg,Jessica van Setten,Aaron Isaacs,Julia Ramírez,Helen R Warren,Sandosh Padmanabhan,Jan A Kors,Rudolf A de Boer,Peter van der Meer,Moritz
Background:The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD.Methods:Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian)
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Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients with Hypertrophic Cardiomyopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-25 Adam S Helms,Andrea D Thompson,Amelia A Glazier,Neha Hafeez,Samat Kabani,Juliani Rodriguez,Jaime M Yob,Helen Woolcock,Francesco Mazzarotto,Neal K Lakdawala,Samuel G Wittekind,Alexandre C Pereira,Daniel L Jacoby,Steven D Colan,Euan A Ashley,Sara Saberi,James S Ware,Jodie Ingles,Christopher Semsarian,Michelle Michels,Iacopo Olivotto,Carolyn Y Ho,Sharlene M Day
Background:Pathogenic variants in MYBPC3, encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.Methods:Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified
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Moving Genomics to Routine Care: An Initial Pilot in Acute Cardiovascular Disease. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-26 Zahra Aryan,Attila Szanto,Angeliki Pantazi,Tejaswini Reddi,Carolyn Rheinstein,Winslow Powers,Evan Wilson,Rahul C Deo,Shimul Chowdhury,Lisa Salz,David Dimmock,Shareef Nahas,Wendy Benson,Stephen F Kingsmore,Calum A MacRae,Dana Vuzman
Background:Whole-genome sequencing (WGS) costs are falling, yet, outside oncology, this information is seldom used in adult clinics. We piloted a rapid WGS (rWGS) workflow, focusing initially on estimating power for a feasibility study of introducing genome information into acute cardiovascular care.Methods:A prospective implementation study was conducted to test the feasibility and clinical utility
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Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-30 Akihiro Nomura,Connor A Emdin,Hong Hee Won,Gina M Peloso,Pradeep Natarajan,Diego Ardissino,John Danesh,Heribert Schunkert,Adolfo Correa,Matthew J Bown,Nilesh J Samani,Jeanette Erdmann,Ruth McPherson,Hugh Watkins,Danish Saleheen,Roberto Elosua,Masa-Aki Kawashiri,Hayato Tada,Namrata Gupta,Svati H Shah,Daniel J Rader,Stacey Gabriel,Amit V Khera,Sekar Kathiresan
Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact
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Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 that Are Common in Chinese Patients. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-20 Chee Jian Pua,Nevin Tham,Calvin Wl Chin,Roddy Walsh,Chiea Chuen Khor,Christopher N Toepfer,Giuliana G Repetti,Amanda C Garfinkel,Jourdan F Ewoldt,Paige Cloonan,Christopher S Chen,Shi Qi Lim,Jiashen Cai,Li Yang Loo,Siew Ching Kong,Charleston W K Chiang,Nicola Whiffin,Antonio de Marvao,Pei Min Lio,An An Hii,Cheng Xi Yang,Thu Thao Le,Yasmin Bylstra,Weng Khong Lim,Jing Xian Teo,Kallyandra Padilha,Gabriela
Background:To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.Methods:We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.Results:Singaporean HCM patients had significantly
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LMNA Missense Mutation Causes Nonsense-mediated mRNA Decay and Severe Dilated Cardiomyopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-20 Koichi Kato,Seiko Ohno,Keiko Sonoda,Megumi Fukuyama,Takeru Makiyama,Tomoya Ozawa,Minoru Horie
Background:LMNA is a known causative gene of dilated cardiomyopathy and familial conduction disturbance. Nonsense-mediated mRNA decay, normally caused by nonsense mutations, is a safeguard process to protect cells from deleterious effects of inappropriate proteins from mutated genes. Nonsense-mediated mRNA decay induced by nonstop codon mutations is rare. We investigated the effect of an LMNA missense
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Founder Mutation in N-terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-04 Akl C Fahed,Georges Nemer,Fadi F Bitar,Samir Arnaout,Antoine B Abchee,Manal Batrawi,Athar Khalil,Oussama Abou-Hassan,Steven R DePalma,Barbara McDonough,Mariam T Arabi,James S Ware,Jonathan G Seidman,Christine E Seidman
Background:Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD). Only one mutation (p.Arg21Cys) has been reported in the N terminus of the protein. In model organisms, it impairs PKA (protein kinase A) phosphorylation, increases calcium sensitivity, and causes diastolic
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Clinical Utility of a Phenotype Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-07 Connor L Mattivi,J Martijn Bos,Richard D Bagnall,Natalie Nowak,John R Giudicessi,Steve R Ommen,Christopher Semsarian,Michael J Ackerman
Background:Missense variants in the MYH7-encoded MYH7 (beta myosin heavy chain 7) represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently but have yet to be assessed independently. We set out to assess the performance of the MYH7-specific ACMG guidelines and determine
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The 9p21.3 Coronary Artery Disease Locus Identifies Patients with Treatment Benefit from Bariatric Surgery in the Non-randomized Prospective Controlled Swedish Obese Subjects Study. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-15 Peter Jacobson,Markku Peltonen,Per-Arne Svensson,Magdalena Taube,Johanna C Andersson-Assarsson,Kajsa Sjöholm,Claude Bouchard,Björn Carlsson,Lena M S Carlsson
Background:Sequence variation at chromosome 9p21.3 accounts for 20% of myocardial infarctions (MIs) in several populations. Whereas the risk conferred by the 9p21.3 locus appears to act independently of traditional risk factors, studies suggest that the association between 9p21.3 and MI is modified by glucose homeostasis and lifestyle. We examined if the 9p21.3 variant rs1333049, along with the previously
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Promise and Potential Peril with Lumacaftor for the Trafficking Defective Type 2 Long QT Syndrome-Causative Variants, p.G604S, p.N633S, and p.R685P, Using Patient-Specific Re-Engineered Cardiomyocytes. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-17 Bailey J O'Hare,Cs John Kim,Samantha K Hamrick,Dan Ye,David J Tester,Michael J Ackerman
Background:The KCNH2-encoded Kv11.1 hERG (human ether-a-go-go related gene) potassium channel is a critical regulator of cardiomyocyte action potential duration (APD). The majority of type 2 long-QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, Food and Drug Administration-approved cystic fibrosis protein trafficking chaperone, lumacaftor, has been proposed as novel therapy
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Implications of Genetic Testing in Dilated Cardiomyopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-03 Job A J Verdonschot,Mark R Hazebroek,Ingrid P C Krapels,Michiel T H M Henkens,Anne Raafs,Ping Wang,Jort J Merken,Godelieve R F Claes,Els K Vanhoutte,Arthur van den Wijngaard,Stephane R B Heymans,Han G Brunner
Background:Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome.Methods:This study included
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The Genetics of Circulating Resistin Level, A Biomarker for Cardiovascular Diseases, Is Informed by Mendelian Randomization and the Unique Characteristics of African Genomes. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-02 Karlijn A C Meeks,Ayo P Doumatey,Amy R Bentley,Mateus H Gouveia,Guanjie Chen,Jie Zhou,Lin Lei,Adebowale A Adeyemo,Charles N Rotimi
Background:Resistin, a protein linked with inflammation and cardiometabolic diseases, is one of few proteins for which genome-wide association studies consistently report variants within and near the coding gene (RETN). Here, we took advantage of the reduced linkage disequilibrium in African populations to infer genetic causality for circulating resistin levels by performing genome-wide association
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Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-01 Zuhair N Al-Hassnan,Abdulrahman Almesned,Sahar Tulbah,Ali Alakhfash,Faten Alhadeq,Nadiah Alruwaili,Maarab Alkorashy,Amal Alhashem,Ahmad Alrashdan,Eissa Faqeih,Salwa M Alkhalifi,Zainab Al Humaidi,Sameera Sogaty,Nawal Azhari,Abdulrahman M Bakhaider,Ali Al Asmari,Ali Awaji,Buthaina Albash,Mohammed Alhabdan,Malak A Alghamdi,Walaa Alshuaibi,Raghad Z Al-Hassnan,Abduljabbar Alshenqiti,Aisha Alqahtani,Zarghuna
Background:Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale.Methods:To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy
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Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-13 Mark Trinder; Martine Paquette; Lubomira Cermakova; Matthew R. Ban; Robert A. Hegele; Alexis Baass; Liam R. Brunham
Background:Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence
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Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-14 Lieke M. van den Heuvel; Maxiem O. van Teijlingen; Wilma van der Roest; Irene M. van Langen; Ellen M.A. Smets; J. Peter van Tintelen; Imke Christiaans
Background:Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s)
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Genetic Analysis of Patients with Sickle Cell Anemia and Stroke before 4 Years of Age Suggest an Important Role for APOE. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-14 John N Brewin,Alexander Smith,Riley Cook,Sanjay Tewari,Julie Brent,Sarah Wilkinson,Valentine Brousse,Baba Inusa,Stephan Menzel,David C Rees
Background:Ischemic stroke is a devastating complication affecting children with sickle cell anemia. Genetic factors are likely to be important in determining the risk of stroke but are poorly defined.Methods:We have studied a cohort of 19 children who had an overt ischemic stroke before 4 years of age. We predicted genetic determinants of stroke would be more prominent in this group. We performed
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Metabolic Age Based on the BBMRI-NL 1H-NMR Metabolomics Repository as Biomarker of Age-related Disease Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-14 Erik B. van den Akker; Stella Trompet; Jurriaan J.H. Barkey Wolf; Marian Beekman; H. Eka D. Suchiman; Joris Deelen; Folkert W. Asselbergs; Eric Boersma; Davy Cats; Petra M. Elders; J. Marianne Geleijnse; M. Arfan Ikram; Margreet Kloppenburg; Haillang Mei; Ingrid Meulenbelt; Simon P. Mooijaart; Rob G.H.H. Nelissen; Mihai G. Netea; Brenda W.J.H. Penninx; Mariska Slofstra; Coen D.A. Stehouwer; Morris
Background:The blood metabolome incorporates cues from the environment and the host’s genetic background, potentially offering a holistic view of an individual’s health status.Methods:We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts.Results:Using this resource
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Use of a Genetic Variant Related to Circulating FXa (Activated Factor X) Levels to Proxy the Effect of FXa Inhibition on Cardiovascular Outcomes Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-08-13 Dipender Gill; Stephen Burgess
Coagulation FX (factor X) is a serine protease that catalyzes the formation of fibrin clots. Although this maintains hemostasis, it can also result in pathological thrombi and emboli.1,2 FXa (activated FX) inhibitors are efficacious for preventing deep venous thrombosis, pulmonary embolism,1 and cardioembolic stroke related to nonvalvular atrial fibrillation.2 However, the efficacy of FXa inhibitors
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Multiomics Screening Identifies Molecular Biomarkers Causally Associated with the Risk of Coronary Artery Disease. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-24 Majid Nikpay,Sebastien Soubeyrand,Rasool Tahmasbi,Ruth McPherson
Background:In this study, we aimed to investigate functional mechanisms underlying coronary artery disease (CAD) loci and find molecular biomarkers for CAD.Methods:We devised a multiomics data analysis approach based on Mendelian randomization and utilized it to search for molecular biomarkers causally associated with the risk of CAD within genomic regions known to be associated with CAD.Results:Through
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Genetic Diagnosis and the Severity of Cardiovascular Phenotype in Patients with Elastin Arteriopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-22 Sandar Min,Caroline Kinnear,Lisa C A D'Alessandro,Jade Bouwmeester,Roderick Yao,David Chiasson,Fred Keeley,Seema Mital
Background:Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene (ELN) causes Williams-Beuren syndrome (WBS), while single nucleotide variants in ELN cause nonsyndromic supravalvar aortic stenosis (SVAS). Our objective was to compare cardiovascular disease outcomes in patients with WBS and nonsyndromic SVAS.Methods:Patients (81 WBS, 42 nonsyndromic SVAS)
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Systematic Evaluation of KCNQ1 Variant Using ACMG/AMP Guidelines and Risk Stratification in Long QT Syndrome Type 1. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-09-16 Asami Kashiwa,Takeshi Aiba,Hisaki Makimoto,Keiko Shimamoto,Kenichiro Yamagata,Tsukasa Kamakura,Mitsuru Wada,Koji Miyamoto,Yuko Inoue-Yamada,Kohei Ishibashi,Takashi Noda,Satoshi Nagase,Aya Miyazaki,Heima Sakaguchi,Isao Shiraishi,Nobue Yagihara,Hiroshi Watanabe,Yoshifusa Aizawa,Takeru Makiyama,Hideki Itoh,Kenshi Hayashi,Masakazu Yamagishi,Naotaka Sumitomo,Masao Yoshinaga,Hiroshi Morita,Tohru Ohe,Yoshihiro
Background - Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients.Methods - We classified a pathogenicity of 141 KCNQ1 variants among 927 LQT1
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De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-06-30 Marko T Boskovski,Jason Homsy,Meena Nathan,Lynn A Sleeper,Sarah Morton,Kathryn B Manheimer,Angela Tai,Joshua Gorham,Matthew Lewis,Michael Swartz,George M Alfieris,Emile A Bacha,Mohsen Karimi,David Meyer,Khanh Nguyen,Daniel Bernstein,Angela Romano-Adesman,George A Porter,Elizabeth Goldmuntz,Wendy K Chung,Deepak Srivastava,Jonathan R Kaltman,Martin Tristani-Firouzi,Richard Lifton,Amy E Roberts,J William
Background:De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.Methods:We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease
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Genetic Risk Scores for Complex Disease Traits in Youth. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-06-11 Tian Xie,Bin Wang,Ilja M Nolte,Peter J van der Most,Albertine J Oldehinkel,Catharina A Hartman,Harold Snieder
Background:For most disease-related traits the magnitude of the contribution of genetic factors in adolescents remains unclear.Methods:Twenty continuous traits related to anthropometry, cardiovascular and renal function, metabolism, and inflammation were selected from the ongoing prospective Tracking Adolescents’ Individual Lives Survey cohort in the Netherlands with measurements of up to 5 waves from
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Genetic Basis and Prognostic Value of Exercise QT Dynamics. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-06-11 Stefan van Duijvenboden,Julia Ramírez,William J Young,Borbala Mifsud,Michele Orini,Andrew Tinker,Patricia B Munroe,Pier D Lambiase
Background:Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated.Methods:QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association
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Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-06-29 Keiichi Hirono,Yukiko Hata,Nariaki Miyao,Mako Okabe,Shinya Takarada,Hideyuki Nakaoka,Keijiro Ibuki,Sayaka Ozawa,Hideki Origasa,Naoki Nishida,Fukiko Ichida,
Background:Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort.Methods:We enrolled 206
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SOS1 Gain-of-Function Variants in Dilated Cardiomyopathy. Circ. Genom. Precis. Med. (IF 4.063) Pub Date : 2020-06-30 Jason R Cowan,Lorien Salyer,Nathan T Wright,Daniel D Kinnamon,Pedro Amaya,Elizabeth Jordan,Michael J Bamshad,Deborah A Nickerson,Ray E Hershberger
Background:Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis.Methods:Exome sequencing was performed on 412 probands and family members from our