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Genetic Associations with Valvular Calcification and Aortic Stenosis

Thanassoulis, George; Campbell, Catherine Y.; Owens, David S.; Smith, Gustav LU ; Smith, Albert V.; Peloso, Gina M.; Kerr, Kathleen F.; Pechlivanis, Sonali; Budoff, Matthew J. and Harris, Tamara B., et al. (2013) In New England Journal of Medicine 368(6). p.503-512
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.... (More)
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.) (Less)
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New England Journal of Medicine
volume
368
issue
6
pages
503 - 512
publisher
Massachusetts Medical Society
external identifiers
  • wos:000314494100001
  • scopus:84873513160
ISSN
0028-4793
DOI
10.1056/NEJMoa1109034
language
English
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yes
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2d96888d-3c13-44e7-a265-8b7dc5567b02 (old id 3589855)
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http://www.ncbi.nlm.nih.gov/pubmed/23388002
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2013-03-20 14:54:35
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2019-03-19 01:23:48
@article{2d96888d-3c13-44e7-a265-8b7dc5567b02,
  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 = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P&lt;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.)},
  author       = {Thanassoulis, George and Campbell, Catherine Y. and Owens, David S. and Smith, Gustav and Smith, Albert V. and Peloso, Gina M. and Kerr, Kathleen F. and Pechlivanis, Sonali and Budoff, Matthew J. and Harris, Tamara B. and Malhotra, Rajeev and O'Brien, Kevin D. and Kamstrup, Pia R. and Nordestgaard, Borge G. and Tybjaerg-Hansen, Anne and Allison, Matthew A. and Aspelund, Thor and Criqui, Michael H. and Heckbert, Susan R. and Hwang, Shih-Jen and Liu, Yongmei and Sjögren, Marketa and vanderPals, Jesper and Kaelsch, Hagen and Muehleisen, Thomas W. and Noethen, Markus M. and Cupples, L. Adrienne and Caslake, Muriel and Di Angelantonio, Emanuele and Danesh, John and Rotter, Jerome I. and Sigurdsson, Sigurdur and Wong, Quenna and Erbel, Raimund and Kathiresan, Sekar and Melander, Olle and Gudnason, Vilmundur and O'Donnell, Christopher J. and Post, Wendy S.},
  issn         = {0028-4793},
  language     = {eng},
  number       = {6},
  pages        = {503--512},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Genetic Associations with Valvular Calcification and Aortic Stenosis},
  url          = {http://dx.doi.org/10.1056/NEJMoa1109034},
  volume       = {368},
  year         = {2013},
}