Department of Medicine and the Research Institute, McGill University Health Centre, Montreal.
N Engl J Med. 2013 Feb 7;368(6):503-12. doi: 10.1056/NEJMoa1109034.
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
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.
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.
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.).
关于瓣膜钙化的遗传贡献，目前的信息有限，而瓣膜钙化是临床瓣膜疾病的重要前兆。
我们通过计算机断层扫描（CT）检测到 6942 名参与者存在主动脉瓣钙化（作为研究存在主动脉瓣钙化的指标），以及 3795 名参与者存在二尖瓣环钙化（作为研究存在二尖瓣环钙化的指标），确定了与这两种情况相关的全基因组关联；本分析的研究人群包括参加 Cohorts for Heart and Aging Research in Genomic Epidemiology 联盟的三个队列中的白种欧洲人后裔（发现人群）。在具有 CT 检测到的瓣膜钙化或临床主动脉瓣狭窄的独立队列中，对发现的结果进行了复制。
脂蛋白（a）（LPA）基因座的一个 SNP（rs10455872）与主动脉瓣钙化的存在达到全基因组显著水平（每个等位基因的优势比，2.05；P=9.0×10(-10)），这一发现也在其他白种欧洲人、非裔美国人以及西班牙裔美国人队列中得到了复制（所有比较的 P<0.05）。通过 LPA 基因型预测的 Lp(a)水平也与主动脉瓣钙化相关，这支持了 Lp(a)的因果作用。在前瞻性分析中，LPA 基因型与大型瑞典队列中的主动脉瓣狭窄发病（每个等位基因的风险比，1.68；95%置信区间[CI]，1.32 至 2.15）和主动脉瓣置换（风险比，1.54；95%CI，1.05 至 2.27）相关；在独立的丹麦队列中，主动脉瓣狭窄发病的关联也得到了复制。两个位于促炎基因 IL1F9 附近的 SNPs（rs17659543 和 rs13415097）与二尖瓣环钙化达到全基因组显著水平（P=1.5×10(-8)和 P=1.8×10(-8)），但这些发现并未得到一致的复制。
LPA 基因座的遗传变异，通过 Lp(a)水平介导，与多种族人群的主动脉瓣钙化以及临床主动脉瓣狭窄的发病相关。（由美国国立心肺血液研究所等资助）。
