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Genetic associations with valvular calcification and aortic stenosis.

Publication ,  Journal Article
Thanassoulis, G; Campbell, CY; Owens, DS; Smith, JG; Smith, AV; Peloso, GM; Kerr, KF; Pechlivanis, S; Budoff, MJ; Harris, TB; Malhotra, R ...
Published in: N Engl J Med
February 7, 2013

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.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

February 7, 2013

Volume

368

Issue

6

Start / End Page

503 / 512

Location

United States

Related Subject Headings

  • Tomography, X-Ray Computed
  • Polymorphism, Single Nucleotide
  • Mitral Valve
  • Middle Aged
  • Mendelian Randomization Analysis
  • Male
  • Lipoprotein(a)
  • Linear Models
  • Humans
  • Heart Valve Diseases
 

Citation

APA
Chicago
ICMJE
MLA
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Thanassoulis, G., Campbell, C. Y., Owens, D. S., Smith, J. G., Smith, A. V., Peloso, G. M., … CHARGE Extracoronary Calcium Working Group, . (2013). Genetic associations with valvular calcification and aortic stenosis. N Engl J Med, 368(6), 503–512. https://doi.org/10.1056/NEJMoa1109034
Thanassoulis, George, Catherine Y. Campbell, David S. Owens, J Gustav Smith, Albert V. Smith, Gina M. Peloso, Kathleen F. Kerr, et al. “Genetic associations with valvular calcification and aortic stenosis.N Engl J Med 368, no. 6 (February 7, 2013): 503–12. https://doi.org/10.1056/NEJMoa1109034.
Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013 Feb 7;368(6):503–12.
Thanassoulis, George, et al. “Genetic associations with valvular calcification and aortic stenosis.N Engl J Med, vol. 368, no. 6, Feb. 2013, pp. 503–12. Pubmed, doi:10.1056/NEJMoa1109034.
Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, Harris TB, Malhotra R, O’Brien KD, Kamstrup PR, Nordestgaard BG, Tybjaerg-Hansen A, Allison MA, Aspelund T, Criqui MH, Heckbert SR, Hwang S-J, Liu Y, Sjogren M, van der Pals J, Kälsch H, Mühleisen TW, Nöthen MM, Cupples LA, Caslake M, Di Angelantonio E, Danesh J, Rotter JI, Sigurdsson S, Wong Q, Erbel R, Kathiresan S, Melander O, Gudnason V, O’Donnell CJ, Post WS, CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013 Feb 7;368(6):503–512.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

February 7, 2013

Volume

368

Issue

6

Start / End Page

503 / 512

Location

United States

Related Subject Headings

  • Tomography, X-Ray Computed
  • Polymorphism, Single Nucleotide
  • Mitral Valve
  • Middle Aged
  • Mendelian Randomization Analysis
  • Male
  • Lipoprotein(a)
  • Linear Models
  • Humans
  • Heart Valve Diseases