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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.

Original publication

DOI

10.1161/atvbaha.118.312128

Type

Journal article

Journal

Arteriosclerosis, thrombosis, and vascular biology

Publication Date

06/2019

Volume

39

Pages

1227 - 1233

Addresses

From the Department of Cardiovascular Medicine (M.S.S., X.F., E.E.A., I.J.K.), Mayo Clinic, Rochester, MN.

Keywords

Humans, Coronary Disease, Genetic Predisposition to Disease, Risk Factors, Case-Control Studies, Sequence Analysis, DNA, Gene Frequency, Phenotype, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genetic Variation, Genetic Loci, Genetic Association Studies, Peripheral Arterial Disease