Genetic associations with valvular calcification and aortic stenosis

George Thanassoulis, Catherine Y. Campbell, David S. Owens, J. 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, Børge G. Nordestgaard, Anne Tybjaerg-Hansen, Matthew A. Allison, Thor Aspelund, Michael H. Criqui, Susan R. Heckbert, Shih Jen HwangYongmei Liu, Marketa Sjogren, Jesper Van Der Pals, Hagen Kälsch, Thomas W. Mühleisen, Markus M. Nöthen, 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

Research output: Contribution to journalArticle

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 aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

Original languageEnglish (US)
Pages (from-to)503-512
Number of pages10
JournalNew England Journal of Medicine
Volume368
Issue number6
DOIs
StatePublished - Feb 7 2013

    Fingerprint

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thanassoulis, G., Campbell, C. Y., Owens, D. S., Smith, J. G., Smith, A. V., Peloso, G. M., Kerr, K. F., Pechlivanis, S., Budoff, M. J., Harris, T. B., Malhotra, R., O'Brien, K. D., Kamstrup, P. R., Nordestgaard, B. G., Tybjaerg-Hansen, A., Allison, M. A., Aspelund, T., Criqui, M. H., Heckbert, S. R., ... Post, W. S. (2013). Genetic associations with valvular calcification and aortic stenosis. New England Journal of Medicine, 368(6), 503-512. https://doi.org/10.1056/NEJMoa1109034