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Nat Med. 2019 Aug;25(8):1274-1279. doi: 10.1038/s41591-019-0492-5. Epub 2019 Jul 8.

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

Author information

1
Boston VA Healthcare System, Boston, MA, USA.
2
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
5
VA Informatics and Computing Infrastructure, Department of Veterans Affairs, Salt Lake City Health Care System, Salt Lake City, CT, USA.
6
University of Massachusetts College of Nursing & Health Sciences, Boston, MA, USA.
7
Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial VA Hospital, Bedford, MA, USA.
8
VA Palo Alto Health Care System, Palo Alto, CA, USA.
9
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
10
Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA.
11
Department of Health Law, Policy & Management, Boston University School of Public Health, Boston, MA, USA.
12
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
13
Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.
14
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
15
Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
16
Atlanta VA Health Care System, Decatur, GA, USA.
17
Department of Epidemiology, Emory University Rollins School of Public Health, Emory University School of Medicine, Atlanta, GA, USA.
18
Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
19
Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, Philadelphia, PA, USA.
20
VA Tennessee Valley Healthcare System, Nashville, TN, USA.
21
Vanderbilt University Medical Center, Nashville, TN, USA.
22
Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
23
Boston University School of Medicine, Boston, MA, USA.
24
Phoenix Veterans Affairs Health Care System, Phoenix, AZ, USA.
25
Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
26
Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN, USA.
27
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
28
Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
29
Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
30
Department of Medicine, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
31
Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
32
Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
33
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. damrauer@upenn.edu.
34
Department of Surgery, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. damrauer@upenn.edu.

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.

PMID:
31285632
PMCID:
PMC6768096
[Available on 2020-01-08]
DOI:
10.1038/s41591-019-0492-5
[Indexed for MEDLINE]

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