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Genetic Associations with Valvular Calcification and Aortic Stenosis

Thanassoulis, George ; Campbell, Catherine Y ; Owens, David S ; Smith, J. Gustav ; Smith, Albert V ; Peloso, Gina M ; Kerr, Kathleen F ; Pechlivanis, Sonali ; Budoff, Matthew J ; Harris, Tamara B ; Malhotra, Rajeev ; O'brien, Kevin D ; Kamstrup, Pia R ; Nordestgaard, Børge G ; Tybjaerg - Hansen, Anne ; Allison, Matthew A ; Aspelund, Thor ; Criqui, Michael H ; Heckbert, Susan R ; Hwang, Shih - Jen ; Liu, Yongmei ; Sjogren, Marketa ; Van Der Pals, Jesper ; Kälsch, Hagen ; Mühleisen, Thomas W ; Nöthen, Markus M ; Cupples, L. Adrienne ; Caslake, Muriel ; Di Angelantonio, Emanuele ; Danesh, John ; Rotter, Jerome I ; Sigurdsson, Sigurdur ; Wong, Quenna ; Erbel, Raimund ; Kathiresan, Sekar ; Melander, Olle ; Gudnason, Vilmundur ; O'donnell, Christopher J ; Post, Wendy S

The New England Journal of Medicine, 2013, Vol.368(6), pp.503-512 [Tạp chí có phản biện]

ISSN: 0028-4793 ; E-ISSN: 1533-4406 ; DOI: 10.1056/NEJMoa1109034

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  • Nhan đề:
    Genetic Associations with Valvular Calcification and Aortic Stenosis
  • Tác giả: Thanassoulis, George ; Campbell, Catherine Y ; Owens, David S ; Smith, J. Gustav ; Smith, Albert V ; Peloso, Gina M ; Kerr, Kathleen F ; Pechlivanis, Sonali ; Budoff, Matthew J ; Harris, Tamara B ; Malhotra, Rajeev ; O'brien, Kevin D ; Kamstrup, Pia R ; Nordestgaard, Børge G ; Tybjaerg - Hansen, Anne ; Allison, Matthew A ; Aspelund, Thor ; Criqui, Michael H ; Heckbert, Susan R ; Hwang, Shih - Jen ; Liu, Yongmei ; Sjogren, Marketa ; Van Der Pals, Jesper ; Kälsch, Hagen ; Mühleisen, Thomas W ; Nöthen, Markus M ; Cupples, L. Adrienne ; Caslake, Muriel ; Di Angelantonio, Emanuele ; Danesh, John ; Rotter, Jerome I ; Sigurdsson, Sigurdur ; Wong, Quenna ; Erbel, Raimund ; Kathiresan, Sekar ; Melander, Olle ; Gudnason, Vilmundur ; O'donnell, Christopher J ; Post, Wendy S
  • Là 1 phần của: The New England Journal of Medicine, 2013, Vol.368(6), pp.503-512
  • Mô tả: 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.) In a genomewide association study, a SNP in the LPA locus was significantly associated with aortic-valve calcification; this SNP was prospectively associated with incident aortic stenosis. Mendelian randomization suggested a causal role for lipoprotein(a) in aortic-valve calcification. Valvular calcification precedes the development of valvular stenosis and may represent an important early phenotype for valvular heart disease. Although aortic sclerosis is frequently considered to be a benign condition, it is associated with progression to clinical aortic stenosis1,2 and with increased cardiovascular morbidity and mortality.3 In addition, mitral annular calcification is associated with a risk of cardiovascular disease that is increased by nearly 50%.4 Currently, there are no treatments that prevent or slow the progression of valve disease. Although genetic factors may influence the development of valvular calcification, which tends to run in families,5 the role of common . . .
  • Số nhận dạng: ISSN: 0028-4793 ; E-ISSN: 1533-4406 ; DOI: 10.1056/NEJMoa1109034

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