Genetic associations with valvular calcification and aortic stenosis.
Genetic associations with valvular calcification and aortic stenosis.
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DOI：
10.1056/nejmoa1109034
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发表时间：
2013-02-07
期刊：
影响因子：
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通讯作者：
CHARGE Extracoronary Calcium Working Group
中科院分区：
文献类型：
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作者：
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 SJ;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
瓣膜钙化是临床瓣膜病的重要先兆，目前有关瓣膜钙化的遗传因素的信息有限。我们通过计算机断层扫描(CT)检测，确定了全基因组与主动脉瓣钙化(在6942名参与者中)和二尖瓣环钙化(在3795名参与者中)的存在的相关性；这项分析的研究人群包括来自三个队列的欧洲白人血统的人，他们参与了基因组流行病学中的心脏和老龄化研究联盟(发现人群)。研究结果在CT检测到的瓣膜钙化或临床主动脉狭窄患者的独立队列中重复。脂蛋白(A)(Lpa)基因座中的一个单核苷酸多态(Rs10455872)对主动脉瓣钙化的存在具有全基因组意义(每个等位基因的优势比为2.05；P=9.0×10−10)，这一发现在另外的欧洲白人、非裔美国人和西班牙裔美国人队列中也得到了重复(P<；0.05用于所有比较)。LPA基因决定的Lp(A)水平也与主动脉瓣钙化有关，支持Lp(A)的因果作用。在前瞻性分析中，在一个大型瑞典队列中，LPA基因与发生的主动脉狭窄(每个等位基因的风险比为1.68；95%可信区间[CI]为1.32至2.15)和主动脉瓣置换术(风险比为1.54；95%可信区间为1.05至2.27)相关；在一个独立的丹麦队列中，与发生的主动脉狭窄的关联也被重复。致炎基因IL1F9附近的两个SNP(rs17659543和rs13415097)对二尖瓣环钙化具有全基因组意义(分别为P=1.5×10−8和P=1.8×10−8)，但结果并不一致。LPA基因的遗传变异受Lp(A)水平的影响，与多个民族的主动脉瓣钙化和临床主动脉狭窄有关。(由国家心肺血液研究所等资助。)
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 aorticvalve 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 aorticvalve 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 aorticvalve 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 aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)