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Genetic Associations with Valvular Calcification and Aortic Stenosis

Author:
  • George Thanassoulis
  • Catherine Y. Campbell
  • David S. Owens
  • Gustav Smith
  • Albert V. Smith
  • Gina M. Peloso
  • Kathleen F. Kerr
  • Sonali Pechlivanis
  • Matthew J. Budoff
  • Tamara B. Harris
  • Rajeev Malhotra
  • Kevin D. O'Brien
  • Pia R. Kamstrup
  • Borge G. Nordestgaard
  • Anne Tybjaerg-Hansen
  • Matthew A. Allison
  • Thor Aspelund
  • Michael H. Criqui
  • Susan R. Heckbert
  • Shih-Jen Hwang
  • Yongmei Liu
  • Marketa Sjögren
  • Jesper vanderPals
  • Hagen Kaelsch
  • Thomas W. Muehleisen
  • Markus M. Noethen
  • L. Adrienne Cupples
  • Muriel Caslake
  • Emanuele Di Angelantonio
  • John Danesh
  • Jerome I. Rotter
  • Sigurdur Sigurdsson
  • Quenna Wong
  • Raimund Erbel
  • Sekar Kathiresan
  • Olle Melander
  • Vilmundur Gudnason
  • Christopher J. O'Donnell
  • Wendy S. Post
Publishing year: 2013
Language: English
Pages: 503-512
Publication/Series: New England Journal of Medicine
Volume: 368
Issue: 6
Document type: Journal article
Publisher: Massachusetts Medical Society

Abstract english

Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

Keywords

  • Cardiac and Cardiovascular Systems

Other

Published
  • Hypertension and Cardiovascular Disease
  • Arrhytmias and Cardiac Device treatment
  • Molecular Cardiology
  • ISSN: 0028-4793
E-mail: gustav [dot] smith [at] med [dot] lu [dot] se

Associate professor

Cardiology

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D1232C

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Cardiovascular Epigenetics

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Research project participant

Heart Failure and Mechanical Support

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Molecular Epidemiology and Cardiology

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