Targeted Sequencing Study to Uncover Shared Genetic Susceptibility Between Peripheral Artery Disease and Coronary Heart Disease—Brief Report

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 39 Số 6 - Trang 1227-1233 - 2019
Maya Safarova1, Xiao Fan1, Erin Austin1, Natalie Van Zuydam2, Jemma C. Hopewell3, Daniel J. Schaid4, Iftikhar J. Kullo1,5
1From the Department of Cardiovascular Medicine (M.S.S., X.F., E.E.A., I.J.K.), Mayo Clinic, Rochester, MN.
2Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom (N.v.Z.).
3Nuffield Department of Population Health, Oxford, United Kingdom (J.H.).
4Department of Health Sciences Research (D.J.S.), Mayo Clinic, Rochester, MN
5Gonda Vascular Center (I.J.K.), Mayo Clinic, Rochester, MN

Tóm tắt

Objective— It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results— Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO , and ZEB2 to be associated with PAD ( P <4.5×10 −5 ). At the gene level, the strongest associations were for LPL and SH2B3 . Conclusions— Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.

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Tài liệu tham khảo

10.1056/NEJMcp1507631

10.1016/j.amjcard.2014.06.029

10.1038/ng.2480

10.1056/NEJMoa0902604

10.1001/jama.2009.801

10.1161/CIRCGENETICS.111.961292

10.1161/CIRCGENETICS.110.958371

10.5339/gcsp.2013.10

10.1136/amiajnl-2013-001827

10.1093/bioinformatics/btp324

10.1101/gr.107524.110

10.1002/0471250953.bi1110s43

10.1038/ng.806

10.1186/s13059-016-0974-4

10.1086/519795

10.1038/nature15393

Lee S. SKAT: SNP-set (Sequence) Kernel Association Test. R package version 1.0.1. for the SKAT. http://cran.r-project.org/web/packages/SKAT/index.html.

10.1161/ATVBAHA.110.210385

10.1161/CIRCRESAHA.116.303518

10.1161/CIRCRESAHA.117.312086

10.1038/ng.3396

10.1161/CIRCULATIONAHA.111.033878

10.3389/fgene.2014.00166

10.1096/fj.11-193383

10.1172/JCI39503

10.1038/nature10659

10.1007/s00439-013-1355-7

10.1038/ng.323

10.1186/1471-2350-12-55

10.1101/gr.087577.108

10.1016/j.ajhg.2010.05.004

10.1016/0021-9150(76)90036-8

10.2450/2016.0303-15

10.1111/j.1538-7836.2007.02818.x

10.1093/hmg/ddw037

10.1111/j.1538-7836.2012.04810.x

10.1182/blood-2007-11-122945

10.1371/journal.pgen.1000730

10.1093/hmg/ddq061

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Thông tin xuất bản

Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 39 Số 6

1227-1233

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