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

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.

• Authors: 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 O'Donnell, Sekar Kathiresan, VA Million Veteran Program, Philip S Tsao, Scott M Damrauer
• Journal: Nature medicine (Nat Med) Vol. 25 Issue 8 Pg. 1274-1279 (08 2019) ISSN: 1546-170X [Electronic] United States
• PMID: 31285632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cholesterol, LDL
• Factor Xa Inhibitors
• Receptors, LDL
• factor V Leiden
• Factor V

Topics

• Aged
• Cholesterol, LDL (genetics)
• Factor V (genetics)
• Factor Xa Inhibitors (therapeutic use)
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Middle Aged
• Peripheral Arterial Disease (genetics)
• Receptors, LDL (genetics)
• Veterans