近日，美国宾夕法尼亚大学Scott M. Damrauer研究组在百万退伍军人计划中进行了周围动脉疾病的全基因组关联研究。这一研究成果于2019年8月发表在国际学术期刊《自然—医学》上。

利用电子健康记录数据，研究人员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、非洲和西班牙裔血统退伍军人中约有3200万个带有PAD（外周动脉疾病，31307个病例和211753个对照）的DNA序列突变。结果在来自英国生物库的5117个PAD病例和389291个对照的独立样本中得以重复。研究人员确定了19个PAD基因座，其中18个以前没有报道过。19个位点中的11个与三种血管床（冠状动脉、脑、外周）中的疾病相关，包括LDLR、LPL和LPA，这表明低密度脂蛋白胆固醇、脂蛋白脂酶途径或循环脂蛋白（a）的治疗性调节可能对多种动脉粥样硬化疾病有效。相反，有四种突变似乎对PAD具有特异性，包括F5 p.R506Q，这突出了血栓形成在外周血管床中的致病作用，并为Xa因子抑制作为PAD的治疗策略提供遗传支持。这些研究结果提示冠状动脉，脑和动脉粥样硬化之间的机制相似性和差异，并提供了治疗见解。

据了解，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是未知的。

附：英文原文

Title: Genome-wide association study of peripheral artery disease in the Million Veteran Program

Author: Derek Klarin, Julie Lynch, Krishna Aragam, Mark Chaffin, Themistocles L. Assimes, Jie Huang, Kyung Min Lee, Qing Shao, Jennifer E. Huffman, Pradeep Natarajan, Shipra Arya, Aeron Small, Yan V. Sun, Marijana Vujkovic, Matthew S. Freiberg, Lu Wang, Jinbo Chen, Danish Saleheen, Jennifer S. Lee, Donald R. Miller, Peter Reaven, Patrick R. Alba, Olga V. Patterson, Scott L. DuVall, William E. Boden, Joshua A. Beckman, J. Michael Gaziano, John Concato, Daniel J. Rader, Kelly Cho, Kyong-Mi Chang, Peter W. F. Wilson, Christopher J. ODonnell, Sekar Kathiresan, Philip S. Tsao, Scott M. Damrauer

Issue&Volume: Volume 25 Issue 8, August 2019

Abstract: 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 ~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.

DOI: 10.1038/s41591-019-0492-5

Source:https://www.nature.com/articles/s41591-019-0492-5