Genome-wide association study of peripheral artery disease in the Million Veteran Program
Genome-wide association study of peripheral artery disease in the Million Veteran Program
复制标题
DOI：
10.1038/s41591-019-0492-5
复制
发表时间：
2019-08-01
期刊：
影响因子：
82.9
通讯作者：
Damrauer, Scott M.
中科院分区：
文献类型：
--
作者：
Klarin, Derek;Lynch, Julie;Damrauer, Scott M.
外周动脉疾病(PAD)是心血管疾病发病率和死亡率的主要原因；然而，遗传因素增加PAD风险的程度在很大程度上尚不清楚。使用电子健康记录数据，我们在百万退伍军人计划中进行了一项全基因组关联研究，测试了欧洲、非洲和西班牙裔退伍军人中的3200万个带有PAD的DNA序列变异(31,307例和211,753例对照)。来自英国生物库的5117例PAD病例和389,291名对照组的独立样本重复了这一结果。我们确定了19个PAD基因座，其中18个以前没有报道过。19个基因座中有11个与冠状动脉、脑、外周三个血管床(包括LDLR、LPL和LPA)的疾病相关，提示调节低密度脂蛋白胆固醇、脂蛋白脂酶途径或循环脂蛋白(A)可能对多种动脉粥样硬化性疾病表型有效。相反，包括F5 p.R506Q在内的四个变异体似乎是PAD的特异性变异，突出了外周血管床血栓形成的致病作用，并为抑制凝血因子Xa作为PAD的治疗策略提供了遗传支持。我们的研究结果突出了冠状动脉、脑和外周动脉粥样硬化在机制上的异同，并提供了治疗的见解。
Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing similar to 32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.