Genetic Associations with Valvular Calcification and Aortic Stenosis

George Thanassoulis(National Institutes of Health), Catherine Y. Campbell(Johns Hopkins University), David S. Owens(University of Washington), J. G. Smith(Broad Institute), Albert V. Smith(University of Iceland), Gina M. Peloso(National Institutes of Health), Kathleen F. Kerr(University of Washington), Sonali Pechlivanis(University of Duisburg-Essen), Matthew J. Budoff(University of California, Los Angeles), Tamara B. Harris(National Institutes of Health), Rajeev Malhotra(Harvard University Press), Kevin D. O’Brien(University of Washington), Pia R. Kamstrup(University of Copenhagen), Børge G. Nordestgaard(University of Copenhagen), Anne Tybjærg‐Hansen(University of Copenhagen), Matthew Allison(University of California San Diego), Thor Aspelund(University of Iceland), Michael H. Criqui(University of California San Diego), Susan R. Heckbert(University of Washington), Shih Jen Hwang(National Institutes of Health), Ching‐Ti Liu(Wake Forest University), Marketa Sjögren(Lund University), Jesper van der Pals(Lund University), Hagen Kälsch(Deutsches Herzzentrum München), Thomas W. Mühleisen(Life & Brain (Germany)), Markus M. Nöthen(University of Bonn), L. Adrienne Cupples(National Institutes of Health), Muriel Caslake(University of Glasgow), Emanuele Di Angelantonio(University of Cambridge), John Danesh(University of Cambridge), Jerome I. Rotter(Cedars-Sinai Medical Center), Sigurður Sigurðsson(Icelandic Heart Association), Quenna Wong(University of Washington), Raimund Erbel(Deutsches Herzzentrum München), Sekar Kathiresan(National Institutes of Health), Olle Melander(Lund University), Vilmundur Guðnason(University of Iceland), Christopher J. O’Donnell(National Institutes of Health), Wendy S. Post(Johns Hopkins University)
New England Journal of Medicine
February 6, 2013
10.1056/nejmoa1109034
Cited by 968Open Access
Full Text

Abstract

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=9.0×10(-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=1.5×10(-8) and P=1.8×10(-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.).

Related Papers

No related papers found

Powered by citation graph analysis