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

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

Nature medicine, 2019-08, Vol.25 (8), p.1274-1279 [Periódico revisado por pares]

United States: Nature Publishing Group

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Título:
Genome-wide association study of peripheral artery disease in the Million Veteran Program
Autor: Klarin, Derek ; Lynch, Julie ; Aragam, Krishna ; Chaffin, Mark ; Assimes, Themistocles L ; Huang, Jie ; Lee, Kyung Min ; Shao, Qing ; Huffman, Jennifer E ; Natarajan, Pradeep ; Arya, Shipra ; Small, Aeron ; Sun, Yan V ; Vujkovic, Marijana ; Freiberg, Matthew S ; Wang, Lu ; Chen, Jinbo ; Saleheen, Danish ; Lee, Jennifer S ; Miller, Donald R ; Reaven, Peter ; Alba, Patrick R ; Patterson, Olga V ; DuVall, Scott L ; Boden, William E ; Beckman, Joshua A ; Gaziano, J Michael ; Concato, John ; Rader, Daniel J ; Cho, Kelly ; Chang, Kyong-Mi ; Wilson, Peter W F ; O'Donnell, Christopher J ; Kathiresan, Sekar ; Tsao, Philip S ; Damrauer, Scott M
Assuntos: Aged ; Arteriosclerosis ; Atherosclerosis ; Cardiovascular diseases ; Care and treatment ; Cholesterol ; Cholesterol, LDL - genetics ; Deoxyribonucleic acid ; DNA ; DNA sequencing ; Electronic health records ; Electronic medical records ; Factor V - genetics ; Factor Xa Inhibitors - therapeutic use ; Genetic aspects ; Genetic factors ; Genetic Predisposition to Disease ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Humans ; Lipase ; Lipoprotein lipase ; Lipoproteins ; Loci ; Low density lipoprotein receptors ; Medical records ; Middle Aged ; Morbidity ; Nucleotide sequence ; Nucleotide sequencing ; Peripheral Arterial Disease - genetics ; Peripheral vascular diseases ; Phenotypes ; Receptors, LDL - genetics ; Risk factors ; Technology application ; Thromboembolism ; Thrombosis ; Vascular diseases ; Veterans
É parte de: Nature medicine, 2019-08, Vol.25 (8), p.1274-1279
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Critical revision of the manuscript for important intellectual content: D.K., T.L.A., Y.V.S., K.C., P.N., D.J.R., K.C., K.-M.C., C.J.O., J.A.B., M.S.F., O.V.P., P.W.W., S.K., P.S.T., S.M.D.
P.S.T and S.M.D jointly supervised this work
Concept and design: D.K., J.L., T.L.A., K.A., M.C., M.S.F., J.A.B., J.M.G., J.C., D.J.R., K.C., K.-M.C., P.W.F.W., C.J.O., S.K., P.S.T., S.M.D.
Drafting of the manuscript: D.K., P.S.T., S.M.D.
J.C. is currently at the Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. The content of this manuscript does not represent the views or policies of the FDA.
Equal contributions statement
Administrative, technical, or material support: D.K., P.N., Y.V.S, M.S.F., J.C., J.A.B., J.C., J.M.G., D.J.R., K.C., K.-M.C., C.J.O., P.W.F.W., S.K., P.S.T., S.M.D.
Acquisition, analysis, or interpretation of data: D.K., J.L., K.A., M.C., T.L.A., J.H., K.M.L., Q.S., J.E.H., P.N., S.A., A.S., Y.V.S., M.V., M.S.F., L.W., J.C., D.S., J.S.L., D.R.M., P.R., P.R.A., O.V.P., S.L.D., W.E.B., J.A.B., J.C., J.M.G., D.J.R., K.C., K.-M.C., P.W.F.W., C.J.O., S.K., P.S.T., S.M.D.
Author Contributions
Present addresses
Descrição: 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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

United States: Nature Publishing Group

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