Abstract
Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. We identified 5 genome-wide significant (Passociation ≤5×10-8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], Pdiabetes=2.5×10-9, Pinteractionwithdiabetes=5.3×10-7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], Psmokers=9.3×10-10, Pinteractionwithsmoking=3.9×10-5). Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
Highlights
Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity
A comparatively smaller subset of the PAD cases was identified based on a mixture of self-reported PAD in patients with clinical evidence of vascular disease and hospital admissions codes related to PAD (Ncases=4914; Table I in the Data Supplement)
We used a population prevalence of 5%14 and found that the heritability for PAD was 55% (SE=9%) which was comparable to the narrow sense heritability of 48% estimated from twin studies.[13]
Summary
We identified genetic variants associated with PAD and meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. We ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. This study made use of data generated from individual studies for which the relevant institutional review board approval had been obtained and all participants consented to inclusion in individual studies. An overview of the study design is illustrated, and the methods are provided in the Data Supplement
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