Genome-Wide Association Study of Peripheral Artery Disease.
van Zuydam NR., Stiby A., Abdalla M., Austin E., Dahlström EH., McLachlan S., Vlachopoulou E., Ahlqvist E., Di Liao C., Sandholm N., Forsblom C., Mahajan A., Robertson NR., Rayner NW., Lindholm E., Sinisalo J., Perola M., Kallio M., Weiss E., Price J., Paterson A., Klein B., Salomaa V., Palmer CNA., Groop P-H., Groop L., McCarthy MI., de Andrade M., Morris AP., Hopewell JC., Colhoun HM., Kullo IJ., GoLEAD Consortium, SUMMIT Consortium None.
BACKGROUND: 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. METHODS: 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 dependent on diabetic or smoking status. RESULTS: 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, CDKN2BAS1, SH2B3-PTPN11, HDAC9, and CHRNA5 loci (which overlapped previously reported associations). Meta-analysis with variants previously association with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 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). CONCLUSIONS: 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.