Publisher: American Heart Association   (Total: 12 journals)   [Sort by number of followers]

Showing 1 - 12 of 12 Journals sorted alphabetically
Arteriosclerosis, Thrombosis and Vascular Biology     Full-text available via subscription   (Followers: 29, SJR: 3.435, CiteScore: 5)
Circulation     Hybrid Journal   (Followers: 186, SJR: 8.95, CiteScore: 9)
Circulation : Arrhythmia and Electrophysiology     Hybrid Journal   (Followers: 14, SJR: 3.225, CiteScore: 4)
Circulation : Cardiovascular Imaging     Hybrid Journal   (Followers: 18, SJR: 3.242, CiteScore: 4)
Circulation : Cardiovascular Interventions     Hybrid Journal   (Followers: 23, SJR: 4.228, CiteScore: 5)
Circulation : Cardiovascular Quality and Outcomes     Hybrid Journal   (Followers: 14, SJR: 2.743, CiteScore: 3)
Circulation : Genomic and Precision Medicine     Hybrid Journal   (Followers: 12, SJR: 2.661, CiteScore: 4)
Circulation : Heart Failure     Hybrid Journal   (Followers: 27, SJR: 4.2, CiteScore: 5)
Circulation Research     Hybrid Journal   (Followers: 32, SJR: 6.813, CiteScore: 9)
Hypertension     Full-text available via subscription   (Followers: 27)
J. of the American Heart Association     Open Access   (Followers: 19, SJR: 2.674, CiteScore: 4)
Stroke     Hybrid Journal   (Followers: 92, SJR: 3.529, CiteScore: 5)
Similar Journals
Journal Cover
Circulation : Genomic and Precision Medicine
Journal Prestige (SJR): 2.661
Citation Impact (citeScore): 4
Number of Followers: 12  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1942-325X - ISSN (Online) 1942-3268
Published by American Heart Association Homepage  [12 journals]
  • Risk of Congenital Heart Defects in Offspring of Affected Mothers and
           Fathers

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      Authors: Nina Øyen Heather A. Boyd Lisbeth Carstensen Lars Søndergaard Jan Wohlfahrt Mads Melbye Department of Epidemiology Research; Statens Serum Institut, Copenhagen, Denmark (N.Ø., H.A.B., L.C., J.W.). Department of Global Public Health Technology, Trondheim, Norway (M.M.). Department of Genetics, Stanford University School of Medicine, Stanford, CA (M.M.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      BACKGROUND:Smaller studies have reported a higher offspring risk of congenital heart defects (CHDs) for mothers with CHDs than for fathers with CHDs. In a large population-based study, we investigated whether offspring risk of CHD differed for mothers and fathers with CHDs.METHODS:All people born in Denmark, 1977 to 2011, with at least 1 registered parent, were included in our cohort (n=2 341 061). Parent-child recurrence of CHDs was evaluated using risk ratios (RRs) comparing risks of CHDs in individuals with and without a parent with a CHD, estimated using log-linear binomial regression.RESULTS:The RRs for any CHD in offspring were 5.39 (95% CI, 4.88–5.96) for mothers and 3.04 (95% CI, 2.59–3.57) for fathers affected with any CHD; the ratio of RRs for mothers versus fathers was 1.82 (P<0.0001). Recurrence RRs for the same cardiac phenotype in parent and offspring were significantly stronger for mothers than for fathers for conotruncal defects (ratio of RRs, 4.98), left ventricular outlet tract obstruction (ratio of RRs, 4.98), and ventricular septal defects (ratio of RRs, 2.51) but not for atrioventricular septal defects (ratio of RRs, 1.06). Birth rates among people with CHDs, relative to the general population, were 18% higher for women than for men, regardless of parental cardiac phenotype.CONCLUSIONS:Recurrence risks of CHDs were significantly greater in the offspring of affected women than in the offspring of affected men. The excess maternal recurrence risks could not be explained by the slightly higher birth rates in women with CHDs.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-24T02:58:22Z
      DOI: 10.1161/CIRCGEN.121.003533
       
  • Multi-Trait Genetic Analysis Reveals Clinically Interpretable Hypertension
           Subtypes

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      Authors: Felix Vaura Hyunkyung Kim Miriam Udler Veikko Salomaa Leo Lahti Teemu Niiranen Department of Internal Medicine; University of Turku, Turku, Finland. (F.V., T.N.) Department of Computing, University of Turku, Turku, Finland. (L.L.) Diabetes Unit Welfare, Helsinki, Finland (V.S., T.N.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Hypertension comprises a heterogeneous range of phenotypes. We asked whether underlying genetic structure could explain a part of this heterogeneity.Methods:Our study sample comprised N=198 148 FinnGen participants (56% women, mean age 58 years) and N=21 168 well-phenotyped FINRISK participants (53% women, mean age 50 years). First, we identified genetic hypertension components with an unsupervised Bayesian non-negative matrix factorization algorithm using public genome-wide association data for 144 genetic hypertension variants and 16 clinical traits. For these components, we computed their (1) cross-sectional associations with clinical traits in FINRISK using linear regression and (2) longitudinal associations with incident adverse outcomes in FinnGen using Cox regression.Results:We observed 4 genetic hypertension components corresponding to recognizable clinical phenotypes: obesity (high body mass index), dyslipidemia (low high-density lipoprotein cholesterol and high triglycerides), hypolipidemia (low low-density lipoprotein cholesterol and low total cholesterol), and Short Stature. In FINRISK, all hypertension components had robust associations with their respective clinical characteristics. In FinnGen, the obesity component was associated with increased diabetes risk (hazard ratio per 1 SD increase 1.08 [Bonferroni corrected CI, 1.05–1.10]) and the hypolipidemia component with increased autoimmune disease risk (hazard ratio per 1 SD increase 1.05 [Bonferroni corrected CI, 1.03–1.07]). In addition, all hypertension components were related to both hypertension and cardiovascular disease.Conclusions:Our unsupervised analysis demonstrates that the genetic basis of hypertension can be understood as a mixture of 4 broad, clinically interpretable components capturing disease heterogeneity. These components could be used to stratify individuals into specific genetic subtypes and, therefore, to benefit personalized health care and pharmaceutical research.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-23T03:11:41Z
      DOI: 10.1161/CIRCGEN.121.003583
       
  • Exploring the Genetic Architecture of Spontaneous Coronary Artery
           Dissection Using Whole-Genome Sequencing

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      Authors: Ingrid Tarr Stephanie Hesselson Siiri E. Iismaa Emma Rath Steven Monger Michael Troup Ketan Mishra Claire M.Y. Wong Pei-Chen Hsu Keerat Junday David T. Humphreys David Adlam Tom R. Webb Anna A. Baranowska-Clarke Stephen E. Hamby Keren J. Carss Nilesh J. Samani Monique Bax Lucy McGrath-Cadell Jason C. Kovacic Sally L. Dunwoodie Diane Fatkin David W.M. Muller Robert M. Graham Eleni Giannoulatou Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia (I.T; S.H, S.E.I, E.R, S.M, M.T, K.M, C.M.Y.W, P.-C.H, K.J, D.T.H, M.B, L.M.-C, J.C.K, S.L.D, D.F, D.W.M.M, R.M.G, E.G.). UNSW Sydney, Kensington, NSW, Australia (S.E.I, E.R, L.M.-C, J.C.K, S.L.D, D.F, D.W.M.M, R.M.G, E.G.). Department of Cardiovascular Sciences, NIHR Leicester Biomedical Research Centre, University of Leicester, United Kingdom (D.A, T.R.W, A.A.B.-C, S.E.H, N.J.S.). Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, United Kingdom (K.J.C.). Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY (J.C.K.). Cardiology Department, St Vincent’s Hospital, Darlinghurst, NSW, Australia (J.C.K, D.F, D.W.M.M, R.M.G.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated. We sought to clarify the genetic cause of SCAD using targeted and genome-wide methods in a cohort of sporadic cases to identify both common and rare disease-associated variants.Methods:A cohort of 91 unrelated sporadic SCAD cases was investigated for rare, deleterious variants in genes associated with either SCAD or CTD, while new candidate genes were sought using rare variant collapsing analysis and identification of novel loss-of-function variants in genes intolerant to such variation. Finally, 2 SCAD polygenic risk scores were applied to assess the contribution of common variants.Results:We identified 10 cases with at least one rare, likely disease-causing variant in CTD-associated genes, although only one had a CTD phenotype. No genes were significantly associated with SCAD from genome-wide collapsing analysis, however, enrichment for TGF (transforming growth factor)-β signaling pathway genes was found with analysis of 24 genes harboring novel loss-of-function variants. Both polygenic risk score demonstrated that sporadic SCAD cases have a significantly elevated genetic SCAD risk compared with controls.Conclusions:SCAD shares some genetic overlap with CTD, even in the absence of any major CTD phenotype. Consistent with a complex genetic architecture, SCAD patients also have a higher burden of common variants than controls.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-18T03:42:34Z
      DOI: 10.1161/CIRCGEN.121.003527
       
  • Arrhythmogenic Right Ventricular Cardiomyopathy Prevalence and Arrhythmic
           

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      Authors: Apurva Sharma Laurens P. Bosman Crystal Tichnell Julie Nanavati Brittney Murray Bareng A.S. Nonyane Harikrishna Tandri Hugh Calkins Cynthia A. James Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S; C.T, B.M, H.T, H.C, C.A.J.). Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, the Netherlands (L.P.B.). Welch Medical Library, Johns Hopkins School of Medicine (J.N.). Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (B.A.S.N.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex cardiomyopathy with autosomal dominant inheritance and age-related incomplete penetrance, characterized by a high risk of sudden cardiac death. Recent professional consensus guidelines recommend clinical cardiac lifelong serial screening for at-risk family members refined only by age, but family genotype might influence necessary screening. Although numerous studies report prevalence of disease and arrhythmia in family members and explore predictors of penetrance and arrhythmic risk, a systematic review consolidating this evidence is lacking.Methods:We searched Medline (PubMed), Embase, The Cochrane Library, and Web of Science for studies that reported prevalence of (1) diagnosis of ARVC per 2010 Task Force Criteria and/or (2) sustained ventricular arrhythmias (VA) in at least 10 family members of definite patients with ARVC.Results:We identified 41 studies, including 36 that reported diagnosis by Task Force Criteria and 22 VA. Meta-analysis of 1359 family members, from 13 unique cohorts showed an average prevalence estimate of 25% for diagnosis as per Task Force Criteria (95% CI, 0.15–0.35, I2=96.44%). Overall prevalence of VA among gene-positive family members was 18% (95% CI, 0.13–0.23, I2=33.25%) in 7 independent studies (n=597). Family genotype was a significant risk factor for diagnosis of both ARVC (odds ratio, 6.91 [95% CI, 1.27–37.70];P=0.0005) and VA (odds ratio, 13.62 [95% CI, 0.91–204.13];P=0.06). Male gender was not associated with disease prevalence (odds ratio, 1.18 [95% CI, 0.72–1.95];P=0.42) or VA (odds ratio, 0.81 [95% CI, 0.51–1.29];P=0.91).Conclusions:The prevalence of ARVC and VA in at-risk family members differs significantly based on family genotype. Although the recent recommendations provide a guideline based only on age, we propose screening every 1 to 2 years for gene-positive family members and every 3 to 5 years for first-degree relatives of gene-elusive cases, as long as they are asymptomatic and not athletes.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-17T01:48:09Z
      DOI: 10.1161/CIRCGEN.121.003530
       
  • Familial Recurrence Patterns in Congenitally Corrected Transposition of
           the Great Arteries: an International Study

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      Authors: Marine Tortigue Lynne E. Nield Matilde Karakachoff Christopher J. McLeod Emre Belli Sonya Babu-Narayan Solène Prigent Angèle Boet Miriam Conway Robert W. Elder Magalie Ladouceur Paul Khairy Eva Kowalik David M. Kalfa David J. Barron Shafi Mussa Anita Hiippala Joel Temple Sylvia Abadir Laurianne Le Gloan Matthias Lachaud Shubhayan Sanatani Jean-Benoit Thambo Céline Grunenwald Gronier Pascal Amedro Guy Vaksmann Anne Charbonneau Linda Koutbi Caroline Ovaert Ali Houeijeh Nicolas Combes Philippe Maury Guillaume Duthoit Bérengère Hiel Christopher C. Erickson Caroline Bonnet George F. Van Hare Christian Dina Clément Karsenty Emmanuelle Fournier Mathieu Le Bloa Robert H. Pass Leonardo Liberman Juha-Matti Happonen James C. Perry Bénédicte Romefort Nadir Benbrik Quentin Hauet Alain Fraisse Michael A. Gatzoulis Dominic J. Abrams Anne M. Dubin Siew Yen Ho Richard Redon Emile A. Bacha Jean-Jacques Schott Alban-Elouen Baruteau Nantes Université; CHU Nantes, CNRS, INSERM, l’institut du thorax, France (M.T., L.L.G., C.D., R.R., J.-J.S., A.-E.B.). Nantes Université, CHU Nantes, Department of Pediatric Cardiology Complex Diseases of the Heart-ERN GUARD-Heart (R.R., J.-J.S., A.-E.B.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns.Methods:An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands.Results:Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia.Conclusions:ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-12T01:50:18Z
      DOI: 10.1161/CIRCGEN.121.003464
       
  • Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial
           Hypercholesterolemia Cascade Screening Program

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      Authors: Mauricio Teruo Tada Viviane Zorzanelli Rocha Isabella Ramos Lima Théo Gremen Mimary Oliveira Ana Paula Chacra Marcio Hiroshi Miname Valéria Sutti Nunes Edna Regina Nakandakare Maria Helane Costa Gurgel Castelo Cinthia Elim Jannes Raul D. Santos José Eduardo Krieger Alexandre Costa Pereira Laboratory of Genetics; Molecular Cardiolog, University of São Paulo Medical School Hospital.y (LIM13) (M.T.T., I.R.L., T.G.M.O., C.E.J., J.E.K., A.C.P.) Lipid Clinic, Heart Institute (InCor), University of São Paulo Medical School Hospital. (V.Z.R., A.P.C., M.H.M., R.D.S.) Laboratório de Lípides (LIM10), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo (V.S.N., E.R.N.). Medical School, Federal University of Ceará, Fortaleza (M.H.C.G.C.). Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil (R.D.S.). Genetics Department, Harvard Medical School, Boston, MA (A.C.P.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants inABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program.Methods:From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for theABCG5/8genes. Clinical and laboratory characteristics of affected individuals were determined.Results:Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant forABCG5/ABCG8genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean β-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122–521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities.Conclusions:Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-12T01:48:56Z
      DOI: 10.1161/CIRCGEN.121.003390
       
  • Genetic Basis of Left Ventricular Noncompaction

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      Authors: Pakdee Rojanasopondist Leigh Nesheiwat Sebastian Piombo George A. Porter Mindong Ren Colin K.L. Phoon Division of Pediatric Cardiology; Department of Pediatrics, NYU Grossman School of Medicine, NY. (P.R., L.N., S.P., C.K.L.P.) Departments of Anesthesiology Cell Biology, NYU Grossman School of Medicine, NY. (M.R.) Division of Pediatric Cardiology, Department of Pediatrics, University of Rochester School of Medicine, NY (G.A.P.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Left ventricular noncompaction (LVNC) is the third most common pediatric cardiomyopathy characterized by a thinned myocardium and prominent trabeculations. Next-generation genetic testing has led to a rapid increase in the number of genes reported to be associated with LVNC, but we still have little understanding of its pathogenesis. We sought to grade the strength of the gene-disease relationship for all genes reported to be associated with LVNC and identify molecular pathways that could be implicated.Methods:Following a systematic PubMed review, all genes identified with LVNC were graded using a validated, semi-quantitative system based on all published genetic and experimental evidence created by the Clinical Genome Resource (ClinGen). Genetic pathway analysis identified molecular processes and pathways associated with LVNC.Results:We identified 189 genes associated with LVNC: 11 (6%) were classified as definitive, 21 (11%) were classified as moderate, and 140 (74%) were classified as limited, but 17 (9%) were classified as no evidence. Of the 32 genes classified as definitive or moderate, the most common gene functions were sarcomere function (n=11; 34%), transcriptional/translational regulator (n=6; 19%), mitochondrial function (n=3; 9%), and cytoskeletal protein (n=3; 9%). Furthermore, 18 (56%) genes were implicated in noncardiac syndromic presentations. Lastly, 3 genetic pathways (cardiomyocyte differentiation via BMP receptors, factors promoting cardiogenesis in vertebrates, and Notch signaling) were found to be unique to LVNC and not overlap with pathways identified in dilated cardiomyopathy and hypertrophic cardiomyopathy.Conclusions:LVNC is a genetically heterogeneous cardiomyopathy. Distinct from dilated or hypertrophic cardiomyopathies, LVNC appears to arise from abnormal developmental processes.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-12T01:47:21Z
      DOI: 10.1161/CIRCGEN.121.003517
       
  • Pharmacogenomic Study of Statin-Associated Muscle Symptoms in the ODYSSEY
           OUTCOMES Trial

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      Authors: William A. Murphy Nan Lin Amy Damask Gregory G. Schwartz P. Gabriel Steg Michael Szarek Poulabi Banerjee Sergio Fazio Garen Manvelian Robert Pordy Alan R. Shuldiner Charles Paulding Division of Pharmacotherapy; Epidemiology, SUNY Downstate School of Public Health, Brooklyn, NY (M.S.). CPC Clinical Research, Aurora, CO (M.S.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Statin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the p.Val174Ala missense variant inSLCO1B1and SAMS in simvastatin-treated subjects; however, evidence for genetic predictors of SAMS in atorvastatin- or rosuvastatin-treated subjects is currently lacking.Methods:ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; n=18 924) was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of alirocumab (a PCSK9 [proprotein convertase subtilisin kexin 9] inhibitor) in acute coronary syndrome patients receiving high-intensity statin therapy. The goal of this pharmacogenomic analysis was to identify genetic variants associated with atorvastatin- and rosuvastatin-mediated SAMS among ODYSSEY OUTCOMES subjects who consented to participate in the genetic study (n=11 880). We performed multi-ancestry exome-wide and genome-wide association studies and gene burden analysis across 2 phenotypes (clinical SAMS [n=10 617] and creatine kinase [n=9630] levels).Results:A novel genome-wide significant association for an intronic variant (rs6667912) located withinTMEM9(odds ratio [95% CI], 1.39 [1.24–1.55];P=3.71×10−8) for patients with clinical SAMS (cases=894, controls=9723) was identified. This variant is located ≈30 kb upstream ofCACNA1S, a locus associated with severe SAMS. We replicated 2 loci, atLINC0093andLILRB5, previously associated with creatine kinase levels during statin treatment. No association was observed between p.Val174Ala (rs4149056) inSLCO1B1and SAMS (odds ratio [95% CI], 1.03 [0.90–1.18];P=0.69).Conclusions:This study comprises the largest discovery exome-wide and genome-wide association studies for atorvastatin- or rosuvastatin-mediated SAMS to date. These novel genetic findings may provide biological/mechanistic insight into this drug-induced toxicity, and help identify at-risk patients before selection of lipid-lowering therapies.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-11T02:38:08Z
      DOI: 10.1161/CIRCGEN.121.003503
       
  • Discordance Between Germline and Blood Mosaicism in Calmodulinopathy

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      Authors: Zahurul A. Bhuiyan Amnah Bdier Jumana Y. Al-Aama Tatiana Abramova Alfred L. George Unité de Recherche Cardiogénétique, Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (Z.A.B.). Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. (A.B; J.Y.A.-A.) Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. (J.Y.A.-A.) Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (T.A, A.L.G.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-11T02:36:42Z
      DOI: 10.1161/CIRCGEN.121.003695
       
  • Pathogenicity Assignment of Variants in Genes Associated With Cardiac
           Channelopathies Evolve Toward Diagnostic Uncertainty

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      Authors: Michael B. Rosamilia Isa M. Lu Andrew P. Landstrom Division of Pediatric Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, NC. (M.B.R; I.M.L, A.P.L.) Department of Cell Biology, Duke University School of Medicine, Durham, NC. (A.P.L.)
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Accurately determining variant pathogenicity is critical in the diagnosis of cardiac channelopathies; however, it remains unknown how variant pathogenicity status changes over time. Our aim is to use a comprehensive analysis of ClinVar to understand mutability of variant evaluation in channelopathy-associated genes to inform clinical decision-making around variant calling.Methods:We identified 10 genes (RYR2, CASQ2, KCNQ1, KCNH2, SCN5A, CACNA1C, CALM1, CALM2, CALM3, TRDN) strongly associated with cardiac channelopathies, as well as 3 comparison gene sets (disputed long QT syndrome, sudden unexpected death in epilepsy, and all ClinVar). We comprehensively analyzed variant pathogenicity calls over time using the ClinVar database with Rstudio. Analyses focused on the frequency and directionality of clinically meaningful changes in disease association, defined as a change from one of the following three categories to another: likely benign/benign, conflicting evidence of pathogenicity/variant of uncertain significance, and likely pathogenic/pathogenic.Results:In total, among channelopathy-associated genes, there were 9975 variants in ClinVar and 8.4% had a clinically meaningful change in disease association at least once over the past 10 years, as opposed to 4.9% of all ClinVar variants. The 3 channelopathy-associated genes with the most variants undergoing a clinically significant change wereKCNQ1(20.9%), SCN5A(11.2%), andKCNH2(10.1%). Ten of the 12 included genes had variant evaluations that trended toward diagnostic uncertainty over time. Specifically, channelopathy-associated gene variants with either pathogenic/likely pathogenic or benign/likely benign assignments were 5.6× and 2×, respectively, as likely to be reevaluated to conflicting/variant of uncertain significance compared to the converse.Conclusions:Over the past 10 years, 8.4% of variants in channelopathy-associated genes have changed pathogenicity status with a decline in overall diagnostic certainty. Ongoing clinical and genetic variant follow-up is needed to account for presence of clinically meaningful change in variant pathogenicity assignment over time.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-11T02:23:37Z
      DOI: 10.1161/CIRCGEN.121.003491
       
  • Communal Coping as a Strategy to Enhance Family Engagement in Dilated
           Cardiomyopathy

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      Authors: Wylie Burke Shelly R. Hovick Elizabeth Jordan Hanyu Ni Daniel D. Kinnamon Ray E. Hershberger Department of Bioethics; Lung Research Institute, Ohio State University Wexner Medical Center, Columbus. (E.J., H.N., D.D.K., R.E.H.) Department of Internal Medicine, Division of Cardiovascular Medicine, Ohio State University Wexner Medical Center, Columbus. (R.E.H.)
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Assuring that relatives are informed about a genetic diagnosis and have appropriate medical follow-up can be challenging. We hypothesize that communal coping (CC)—an approach in which a group views a stressor (such as a new genetic diagnosis) as our problem, versus my or your problem, and takes joint action to address it—can help families to address this challenge. A better understanding of CC could also inform counseling interventions to promote CC and family follow-up.Methods:In the Dilated Cardiomyopathy (DCM) PM study (Precision Medicine), living first-degree relatives of DCM probands were invited to undergo clinical screening; 31% of these did so. This research program offers the opportunity to determine the frequency of CC in DCM families, assess whether CC attitudes and actions occurred more commonly among families in which family members participated, and conduct prospective follow-up to evaluate family coping and counseling needs over time.Results:The proposed studies will provide evidence about the frequency of CC attitudes and actions among DCM families, assess the association of CC with increased family follow-up, and identify counseling needs related to family follow-up.Conclusions:The DCM PM study offers an opportunity to test the hypothesis that CC contributes to increased family follow-up and generate evidence to inform counseling interventions to encourage such follow-up.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-10T02:49:21Z
      DOI: 10.1161/CIRCGEN.121.003541
       
  • Population Prevalence of Premature Truncating Variants in Plakophilin-2
           and Association With Arrhythmogenic Right Ventricular Cardiomyopathy: a UK
           Biobank Analysis

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      Authors: Robyn J. Hylind Alexandre C. Pereira Daniel Quiat Stephanie F. Chandler Thomas M. Roston William T. Pu Vassilios J. Bezzerides Jonathan G. Seidman Christine E. Seidman Dominic J. Abrams Inherited Cardiac Arrhythmia Program; Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston MA. (R.J.H., D.Q., S.F.C., T.M.R., W.T.P., V.J.B., D.J.A.) Department of Genetics, Harvard Medical School, Boston MA. (A.C.P., D.Q., J.G.S., C.E.S.) Cardiovascular Division, Brigham Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, Brazil (A.C.P.). Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Truncating variants in the desmosomal genePKP2(PKP2tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity.Methods:We identified individuals withPKP2tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. ThePKP2tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI) were assessed.Results:PKP2tv were identified in 193/200 643 (0.10%) UKB participants, with 47 uniquePKP2tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 withPKP2tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10−4). The ARVC cohort included 487 ARVC probands with 144 distinctPKP2tv, with 25PKP2tv common to both cohorts. The odds ratio for ARVC for the 25 commonPKP2tv was 0.047 (95% CI, 0.001–0.268;P=2.43×10−6), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiatePKP2tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those withPKP2tv (7.9% versus 4.3%; odds ratio, 2.11;P=0.005).Conclusions:PKP2tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of howPKP2tv cause ARVC in combination with associated genetic and environmental risk factors.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-10T02:47:47Z
      DOI: 10.1161/CIRCGEN.121.003507
       
  • Integrative Analysis of Circulating Metabolite Levels That Correlate With
           Physical Activity and Cardiorespiratory Fitness

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      Authors: Matthew Nayor Ariel Chernofsky Patricia E. Miller Nicole L. Spartano Venkatesh L. Murthy Rajeev Malhotra Nicholas E. Houstis Joanne M. Murabito Clary B. Clish Martin G. Larson Ramachandran S. Vasan Ravi V. Shah Gregory D. Lewis Sections of Cardiovascular Medicine & Preventive Medicine; Cardiovascular Medicine, Department of Medicine, Department of Epidemiology, Boston University Schools of Medicine & Public Health & Center for Computing & Data Sciences, Boston University, MA (R.S.V.). Vanderbilt Clinical & Translational Research Center, Cardiology Division, Vanderbilt University Medical Center, Nashville, TN (R.V.S.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-10T02:45:39Z
      DOI: 10.1161/CIRCGEN.121.003592
       
  • Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in
           Myocarditis

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      Authors: Coloma Tirón Oscar Campuzano Anna Fernández-Falgueras Mireia Alcalde Pablo Loma-Osorio Elisabet Zamora Angel Caballero Georgia Sarquella-Brugada Sergi Cesar Luisa Garcia-Cuenllas Ana García Paloma Jordà Elena Arbelo Carlos Tomás-Querol Victor Pineda Daniel Martínez Ramon Brugada Inherited Cardiac Diseases Unit; Department of Cardiology, Hospital Universitari Dr Josep Trueta, Girona, Spain. (C.T., A.F.-F., R.B.) Intensive Cardiac Care Unit, Department of Cardiology, Hospital Universitari Dr Josep Trueta, Girona, Spain. (P.L.-O.) Radiology Department, Hospital Universitari Dr Josep Trueta, Girona, Spain. (V.P.) Medical Science Department, School of Medicine, University of Girona, Spain. (C.T., O.C., P.L.-O., G.S.-B., R.B.) Cardiovascular Genetics Center, IDIBGI, University of Girona, Spain. (O.C., A.F.-F., M.A., R.B.) Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). Biochemistry Molecular Genetics Department, Hospital Clinic, IDIBAPS, University of Barcelona, Spain. (O.C.) Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Spain. (G.S.-B., S.C., L.G.-C.) Cardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (E.Z., A.C.). Medical Science Department, School of Medicine, Universitat Autònoma de Barcelona, Spain (E.Z.). Institut Clínic Cardiovascular, Hospital Clínic, Universitat de Barcelona, Spain. (A.G., P.J., E.A.) Pathology Department, Hospital Clínic, Universitat de Barcelona, Spain. (D.M.) Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain (A.G., P.J., E.A.). Department of Cardiology, Hospital Universitario Arnau de Vilanova, Lleida, Spain (C.T.-Q.). Institut de Recerca Biomèdica de Lleida, Spain (C.T.-Q.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-06T02:21:38Z
      DOI: 10.1161/CIRCGEN.121.003408
       
  • Genetically Predicted Pulse Pressure and Risk of Abdominal Aortic
           Aneurysm: a Mendelian Randomization Analysis

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      Authors: Stephen Burgess Julio A. Chirinos Scott M. Damrauer Dipender Gill Medical Research Council Biostatistics Unit; Cambridge Institute of Public Health, United Kingdom (S.B.). Cardiovascular Epidemiology Unit, Department of Public Health Immunity, St George’s, University of London (D.G.). Novo Nordisk Research Centre Oxford, United Kingdom (D.G.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-06T02:21:03Z
      DOI: 10.1161/CIRCGEN.121.003575
       
  • Blood Pressure Polygenic Scores Are Associated With Apparent
           Treatment-Resistant Hypertension

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      Authors: Joseph H. Breeyear Megan M. Shuey Todd L. Edwards Jacklyn N. Hellwege Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN. (J.H.B; M.M.S, T.L.E, J.N.H.) Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. (M.M.S, J.N.H.) Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. (T.L.E.)
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-06T02:20:30Z
      DOI: 10.1161/CIRCGEN.121.003554
       
  • Congenital Heart Disease Gene: a Curated Database for Congenital Heart
           Disease Genes

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      Authors: Andrian Yang Dimuthu Alankarage Hartmut Cuny Eddie K.K. Ip Moran Almog Jessica Lu Debjani Das Annabelle Enriquez Justin O. Szot David T. Humphreys Gillian M. Blue Joshua W.K. Ho David S. Winlaw Sally L. Dunwoodie Eleni Giannoulatou Victor Chang Cardiac Research Institute, Darlinghurst, Australia (A.Y; D.A, H.C, E.K.K.I, M.A, J.L, D.D, A.E, J.O.S, D.T.H, G.M.B, S.L.D, E.G.). UNSW Sydney, Kensington, Australia (E.K.K.I, J.L, A.E, D.T.H, S.L.D, E.G.). Heart Centre for Children, The Children’s Hospital at Westmead, Australia (G.M.B.). Sydney Medical School, The University of Sydney, Australia (G.M.B.). School of Biomedical Sciences, University of Hong Kong (J.W.K.H.). Laboratory for Data Discovery for Health (D24H), Hong Kong Science Park (J.W.K.H.). Heart Institute, Cincinnati Children’s Hospital Medical Center, OH (D.S.W.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-05-06T02:19:53Z
      DOI: 10.1161/CIRCGEN.121.003539
       
  • Correction to: Cupido et al, Genetically Predicted
           Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From
           Mendelian Randomization

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      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-04-22T05:28:54Z
      DOI: 10.1161/HCG.0000000000000089
       
  • Value of Genetic Testing for Lipoprotein(a) Variants

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      Authors: Anne Langsted Børge G. Nordestgaard Department of Clinical Biochemistry; Medical Sciences, University of Copenhagen, Denmark.
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-03-21T01:56:32Z
      DOI: 10.1161/CIRCGEN.122.003737
       
  • Need for Inclusive Genomic Research

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      Authors: Neesha Krishnan Jodie Ingles Centre for Population Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia (N.K; J.I.). UNSW Sydney, Australia (N.K, J.I.). Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Australia (N.K, J.I.). Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (J.I.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-03-21T01:54:47Z
      DOI: 10.1161/CIRCGEN.122.003736
       
  • Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic
           Variants Independent of Clinically Observed Longitudinal Cholesterol
           Exposure

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      Authors: Shoa L. Clarke Catherine Tcheandjieu Austin T. Hilliard Min Lee Julie Lynch Kyong-Mi Chang Donald Miller Joshua W. Knowles Christopher O’Donnell Phil Tsao Daniel J. Rader Peter W. Wilson Yan V. Sun Michael Gaziano Themistocles L. Assimes VA Palo Alto Health Care system, CA (S.L.C; C.T, A.T.H, P.T, T.L.A.). Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (S.L.C, C.T, A.T.H, J.W.K, P.T, T.L.A.). VA Informatics & Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT (K.M.L, J.L.). College of Nursing & Health Sciences, University of Massachusetts, Boston (J.L.). Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA (K.-M.C.). Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (K.-M.C, D.J.R.). Edith Nourse Rogers Memorial VA Hospital, Bedford, MA (D.M.). Center for Population Health, University of Massachusetts, Lowell, MA (D.M.). Diabetes Research Center, Stanford University School of Medicine, CA. (J.W.K.) Cardiovascular Institute, Stanford University School of Medicine, CA. (J.W.K, P.T, T.L.A.) VA Boston Healthcare System, Boston, MA (C.O, M.G.). Department of Medicine, Harvard Medical School, Boston, MA (C.O.). Atlanta VA Medical Center, Decatur, GA (P.W.W, Y.V.S.). Department of Medicine, Emory University School of Medicine, Atlanta, GA (P.W.W.). Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA (P.W.W, Y.V.S.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered.Methods:We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants inLDLR,APOB, andPCSK9were assessed by custom genotype array.Results:In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24–1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08–1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available.Conclusions:The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-10T07:52:54Z
      DOI: 10.1161/CIRCGEN.121.003501
       
  • Genome-Wide Characterization of a Highly Penetrant Form of
           Hyperlipoproteinemia Associated With Genetically Elevated Cardiovascular
           Risk

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      Authors: Stefan Coassin Kevin Chemello Ilya Khantalin Lukas Forer Patricia Döttelmayer Sebastian Schönherr Rebecca Grüneis Clément Chong-Hong-Fong Brice Nativel Stéphane Ramin-Mangata Antonio Gallo Mathias Roche Beatrix Mühlegger Christian Gieger Annette Peters Johannes Zschocke Catherine Marimoutou Olivier Meilhac Claudia Lamina Florian Kronenberg Valentin Blanchard Gilles Lambert Institute of Genetic Epidemiology; Department of Genetics Pharmacology, Medical University of Innsbruck, Austria. (S.C., L.F., P.D., S.S., R.G., C.L., F.K.) Institute of Human Genetics, Medical University of Innsbruck, Austria. (B.M.) Université de La Réunion, INSERM UMR 1188 DéTROI, Sainte-Clotilde, France (K.C., I.K., C.C.-H.-F., B.N., S.R.-M., A.G., M.R., O.M., V.B., G.L.). CHU de La Réunion, Service de Chirurgie Cardiaque Vasculaire et Thoracique, Saint-Denis, France (I.K.). Research Unit of Molecular Epidemiology (C.G.) Institute of Epidemiology (C.G., A.P.) Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg. German Center for Diabetes Research (DZD), München-Neuherberg (C.G., A.P.). CHU de La Réunion, CIC EC1410, Saint-Pierre, France (C.M., O.M.). Department of Medicine, Centre for Heart Lung Innovation, Providence Healthcare Research Institute, St Paul’s Hospital, University of British Columbia, Vancouver, Canada (V.B.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype.Methods:A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed.Results:Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside theLPAlocus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significantLPAsingle nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of theLPAlocus was omitted.Conclusions:High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals,LPAcan be a major locus driving a very high CAD GRS. This underpins the large contribution of theLPAlocus to the cardiovascular genetic risk in families.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-08T03:45:08Z
      DOI: 10.1161/CIRCGEN.121.003489
       
  • CELSR1 Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left
           Heart Syndrome

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      Authors: Jeanne L. Theis Talha Niaz Rhianna S. Sundsbak Zachary C. Fogarty William R. Bamlet Donald J. Hagler Timothy M. Olson Cardiovascular Genetics Research Laboratory; Mayo Clinic, Rochester, MN. (J.L.T., R.S.S., T.M.O.) Division of Pediatric Cardiology, Department of Pediatric Biostatistics, Department of Quantiative Health Sciences, Mayo Clinic, Rochester, MN. (W.R.B.)
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Whole-genome sequencing in families enables deciphering of congenital heart disease causes. A shared genetic basis for familial bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS) was postulated.Methods:Whole-genome sequencing was performed in affected members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 controls. Data were filtered for rare, predicted-damaging variants that cosegregated with familial BAV and disrupted genes associated with congenital heart disease in humans and mice. Candidate genes were further prioritized by rare variant burden testing in HLHS cases versus controls. Modifier variants in HLHS proband-parent trios were sought to account for the severe developmental phenotype.Results:In 5 BAV families, missense variants in 6 ontologically diverse genes for structural (SPTBN1,PAXIP1, andFBLN1) and signaling (CELSR1,PLXND1, andNOS3) proteins fulfilled filtering metrics.CELSR1, encoding cadherin EGF LAG seven-pass G-type receptor, was identified as a candidate gene in 2 families and was the only gene demonstrating rare variant enrichment in HLHS probands (P=0.003575). HLHS-associatedCELSR1variants included 16 missense, one splice site, and 3 noncoding variants predicted to disrupt canonical transcription factor binding sites, most of which were inherited from a parent without congenital heart disease. Filtering whole-genome sequencing data for rare, predicted-damaging variants inherited from the other parent revealed 2 cases ofCELSR1compound heterozygosity, one case ofCELSR1-CELSR3synergistic heterozygosity, and 4 cases ofCELSR1-MYO15Adigenic heterozygosity.Conclusions:CELSR1is a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway perturbation in congenital heart disease.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-08T03:44:04Z
      DOI: 10.1161/CIRCGEN.121.003523
       
  • Ultra-Rapid Nanopore Whole Genome Genetic Diagnosis of Dilated
           Cardiomyopathy in an Adolescent With Cardiogenic Shock

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      Authors: John E. Gorzynski Sneha D. Goenka Kishwar Shafin Tanner D. Jensen Dianna G. Fisk Megan E. Grove Elizabeth Spiteri Trevor Pesout Jean Monlong Jonathan A. Bernstein Scott Ceresnak Pi-Chuan Chang Jeffrey W. Christle Henry Chubb Kyla Dunn Daniel R. Garalde Joseph Guillory Maura R.Z. Ruzhnikov Chris Wright Courtney J. Wusthoff Katherine Xiong Seth A. Hollander Gerald J. Berry Miten Jain Fritz J. Sedlazeck Andrew Carroll Benedict Paten Euan A. Ashley Stanford University, CA (J.E.G; S.D.G, T.D.J, E.S, J.A.B, S.C, J.W.C, H.C, M.R.Z.R, C.J.W, K.X, S.A.H, G.J.B, E.A.A.) Stanford Health Care, Palo Alto (D.G.F, M.E.G.). Stanford Children’s Health, Palo Alto (K.D.). University of California at Santa Cruz Genomics Institute (K.S, T.P, J.M, M.J, B.P.). Baylor College of Medicine, Houston, TX (F.J.S.). Google Inc, Mountain View, CA (P.-C.C, A.C.). Oxford Nanopore Technologies, United Kingdom (D.R.G, J.G, C.W.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-08T03:42:28Z
      DOI: 10.1161/CIRCGEN.121.003591
       
  • How Communicating Polygenic and Clinical Risk for Atherosclerotic
           Cardiovascular Disease Impacts Health Behavior: an Observational Follow-up
           Study

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      Authors: Elisabeth Widén Nella Junna Sanni Ruotsalainen Ida Surakka Nina Mars Pietari Ripatti Juulia J. Partanen Johanna Aro Pekka Mustonen Tiinamaija Tuomi Aarno Palotie Veikko Salomaa Jaakko Kaprio Jukka Partanen Kristina Hotakainen Pasi Pöllänen Samuli Ripatti Institute for Molecular Medicine Finland; FIMM, HiLIFE, University of Helsinki, Finland. (E.W., N.J., S.R., I.S., N.M., P.R., J.J.P., J.A., T.T., A.P., J.K., S.R.) Research Program Unit, Clinical health care services, Kotka, Finland (P.P.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Prediction tools that combine polygenic risk scores with clinical factors provide a new opportunity for improved prediction and prevention of atherosclerotic cardiovascular disease, but the clinical utility of polygenic risk score has remained unclear.Methods:We collected a prospective cohort of 7342 individuals (64% women, mean age 56 years) and estimated their 10-year risk for atherosclerotic cardiovascular disease both by a traditional risk score and a composite score combining the effect of a polygenic risk score and clinical risk factors. We then tested how returning the personal risk information with an interactive web-tool impacted on the participants’ health behavior.Results:When reassessed after 1.5 years by a clinical visit and questionnaires, 20.8% of individuals at high (>10%) 10-year atherosclerotic cardiovascular disease risk had seen a doctor, 12.4% reported weight loss, 14.2% of smokers had quit smoking, and 15.4% had signed up for health coaching online. Altogether, 42.6% of persons at high risk had made one or more health behavioral changes versus 33.5% of persons at low/average risk such that higher baseline risk predicted a favorable change (OR [CI], 1.53 [1.37–1.72] for persons at high risk versus the rest,P<0.001), with both high clinical (P<0.001) and genomic risk (OR [CI], 1.10 [1.03–1.17],P=0.003) contributing independently.Conclusions:Web-based communication of personal atherosclerotic cardiovascular disease risk-data including polygenic risk to middle-aged persons motivates positive changes in health behavior and the propensity to seek care. It supports integration of genomic information into clinical risk calculators as a feasible approach to enhance disease prevention.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-07T07:57:24Z
      DOI: 10.1161/CIRCGEN.121.003459
       
  • Common Polymorphism That Protects From Cardiovascular Disease Increases
           Fibronectin Processing and Secretion

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      Authors: Sébastien Soubeyrand Paulina Lau Majid Nikpay Anh-Thu Dang Ruth McPherson Atherogenomics Laboratory, University of Ottawa Heart Institute, Canada. (S.S; P.L, M.N, A.-T.D, R.M.) Department of Medicine, Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Canada. (R.M.)
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Fibronectin (FN1) is an essential regulator of homodynamic processes and tissue remodeling that have been proposed to contribute to atherosclerosis. Moreover, recent large-scale genome-wide association studies (GWAS) have linked common genetic variants within theFN1gene to coronary artery disease risk.Methods:Public databases were analyzed by 2-Sample Mendelian Randomization. Expression constructs encoding shortFN1reporter constructs and full-length plasmaFN1variants were introduced in various cell models. Secreted and cellular levels were then analyzed and quantified by SDS-PAGE and fluorescence microscopy. Mass spectrometry and glycosylation analyses were performed to probe possible posttranscriptional differences.Results:Bioinformatic analyses revealed that common coronary artery disease risk single nucleotide polymorphisms in theFN1locus associate with circulating levels of FN1 and that higher FN1 (fibronectin 1) protein levels in plasma are linked to lower coronary artery disease risk. The coronary artery disease-associatedFN1locus encompasses a common polymorphism that translates a L15Q variant situated within the FN1 signal peptide. Introduction of FN1 reporter constructs, differing at position 15, revealed differences in secretion, with the FN1 Q15 variant being less well secreted. Moreover, the L15Q polymorphism was found to alter glycosylation in some cell models but not in human plasma.Conclusions:In addition to providing novel functional evidence implicating FN1 in cardioprotection, these findings demonstrate that a common variant within a secretion signal peptide regulates protein function.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-07T07:56:18Z
      DOI: 10.1161/CIRCGEN.121.003428
       
  • Causative Variants for Inherited Cardiac Conditions in a Southeast Asian
           Population Cohort

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      Authors: Swati Tomar David C. Klinzing Chen Ching Kit Louis Hanqiang Gan Tia Moscarello Chloe Reuter Euan A. Ashley Roger Foo Cardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University Singapore (S.T; D.C.K, C.C.K, L.H.G, R.F.). Cardiovascular Research Institute, National University Heart Centre, National University Health System, Singapore. (S.T, D.C.K, C.C.K, L.H.G, R.F.) Khoo Teck Puat National University Children’s Medical Institute, National University Health System, Singapore. (C.C.K.) Department of Pediatrics, Yong Loo Lin School of Medicine, National University Singapore, Singapore (C.C.K.). Stanford University Medical Center, CA (T.M, C.R, E.A.A.). Genome Institute of Singapore (R.F.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Variable penetrance and late-onset phenotypes are key challenges for classifying causal as well as incidental findings in inherited cardiac conditions. Allele frequencies of variants in ancestry-specific populations, along with clinical variant analysis and interpretation, are critical to determine their true significance.Methods:Here, we carefully reviewed and classified variants in genes associated with inherited cardiac conditions based on a population whole-genome sequencing cohort of 4810 Singaporeans representing Southeast Asian ancestries.Results:Eighty-nine (1.85%) individuals carried either pathogenic or likely pathogenic variants across 25 genes. 51.7% had variants in causal genes for familial hyperlipidemia, but there were also recurrent variants inSCN5AandMYBPC3, causal genes for inherited arrhythmia and cardiomyopathy, which, despite previous reports, we determined to lack criteria for pathogenicity.Conclusions:Our findings highlight the incidence of disease-related variants in inherited cardiac conditions and emphasize the value of large-scale sequencing in specific ancestries. Follow-up detailed phenotyping and analysis of pedigrees are crucial because assigning pathogenicity will significantly affect clinical management for individuals and their family members.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-07T07:54:43Z
      DOI: 10.1161/CIRCGEN.121.003536
       
  • Genome-Wide De Novo Variants in Congenital Heart Disease Are Not
           Associated With Maternal Diabetes or Obesity

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      Authors: Sarah U. Morton Alexandre C. Pereira Daniel Quiat Felix Richter Alexander Kitaygorodsky Jacob Hagen Daniel Bernstein Martina Brueckner Elizabeth Goldmuntz Richard W. Kim Richard P. Lifton George A. Porter Martin Tristani-Firouzi Wendy K. Chung Amy Roberts Bruce D. Gelb Yufeng Shen Jane W. Newburger J.G. Seidman Christine E. Seidman Division of Newborn Medicine; Department of Medicine, Boston Children’s Hospital. (S.U.M.) Department of Cardiology, Boston Children’s Hospital. (D.Q., A.R., J.W.N.) Department of Pediatrics, Harvard Medical School, Boston, MA. (S.U.M., D.Q., A.R., J.W.N.) Department of Genetics, Harvard Medical School, Boston, MA. (A.C.P., J.G.S., C.E.S.) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY. (F.R.) Department of Pediatrics, Mindich Child Health Women’s Hospital, Boston, MA (C.E.S.). Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.
      Background:Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD.Methods:DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium’s CHD GENES study. The frequency of DNVs was compared between subgroups usingttest or linear model.Results:DNV frequencies were compared for 1812 patients with CHD and prenatal history data who were recruited to the Pediatric Cardiac Genomics Consortium’s CHD GENES study. The number of DNVs per CHD patient was higher with exposure to maternal diabetes (76.5 versus 72.1,ttestP=3.03×10−11), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correctionP=0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interactionP=0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30,ttestP=0.86).Conclusions:After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures.REGISTRATION:URL:https://clinicaltrials.gov; NCT01196182.
      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-07T07:53:16Z
      DOI: 10.1161/CIRCGEN.121.003500
       
  • End Stage Mitochondrial Cardiomyopathy and Heart Transplantation Due to
           Biallelic Pathogenic C1QBP Variants

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      Authors: Nicholas S. Wilcox Stuart B. Prenner Marisa Cevasco Courtney Condit Amy Goldstein James T. Peterson Isabella Tondi Resta Matthew Palmer Priti Lal Anjali Tiku Owens Janice Pieretti Theodore G. Drivas Nosheen Reza Division of Cardiovascular Medicine (N.S.W.; S.B.P., A.T.O., J.P., N.R.) Division of Translational Medicine Laboratory Medicine, University of Pennsylvania, Philadelphia (I.T.R., M.P., P.L.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-04T01:56:05Z
      DOI: 10.1161/CIRCGEN.121.003559
       
  • Monomorphic and Polymorphic Ventricular Arrhythmias in Heterozygous
           Calsequestrin-2 Mutation Carriers

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      Authors: Juan Jiménez-Jáimez Mercedes Cabrera Ramos Francisco Bermúdez-Jiménez José Manuel García Pinilla Ainhoa Robles Mezcua Rosa Macías Ruiz Miguel Álvarez Luis Tercedor Cardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain (J.J.-J; F.B.-J, R.M.R, M.A, L.T.). Cardiology Department, Hospital Universitario lozano Blesa, Zaragoza. Spain (J.J.-J, F.B.-J, R.M.R, M.A, L.T.). Instituto de Investigación Biosanitaria ibs, GRANADA, Universidad de Granada, Spain (M.C.R.). Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (F.B.-J.). Cardiology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain (J.M.G.P, A.R.M.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-04T01:54:00Z
      DOI: 10.1161/CIRCGEN.121.003518
       
  • Pregnancy Outcomes in Females With Dilated Cardiomyopathy–Associated
           Rare Genetic Variants

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      Authors: Stacey Peters Paul A James Diane Fatkin Dominica Zentner Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. (S.P; D.Z.) Department of Genomic Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia. (A.P, P.A.J, D.Z.) Department of Medicine, University of Melbourne, Victoria, Australia (S.P, P.A.J, D.Z.). Familial Cancer Centre, Peter MacCallum Centre, Melbourne, Victoria, Australia (P.A.J.). Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia (D.F.). St. Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Australia (D.F.). Cardiology Department, St. Vincent’s Hospital, Sydney, New South Wales, Australia (D.F.).
      Abstract: Circulation: Genomic and Precision Medicine, Ahead of Print.

      Citation: Circulation: Genomic and Precision Medicine
      PubDate: 2022-02-03T08:15:55Z
      DOI: 10.1161/CIRCGEN.121.003540
       
 
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