Abstract
Introduction: GWAS have identified SNPs associated with an increased risk of peripheral artery disease (PAD). We sought to compare the performance of a genetic risk score (GRS) comprised of these SNPs with established clinical risk factors to predict PAD and acute limb ischemia (ALI) across five RCTs in cardiometabolic disease. Given high prevalence of coronary artery disease (CAD) in patients with PAD, we also evaluated the performance of the GRS for incident myocardial infarction (MI). Methods: Pts from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. ALI and MI were adjudicated by a blinded CEC comprised of vascular medicine specialists and cardiologists. A previously validated GRS ( Nature Medicine 2019) of 19 SNPs associated with PAD was calculated for each pt. ORs for PAD were calculated across genetic risk groups. HRs adjusted for clinical risk factors were calculated for ALI and incident MI. Results: Of 51,729 total pts included in this analysis, 5,149 (10%) had PAD at baseline. Pts in the top 20% of GRS had 47% higher odds of having PAD compared with those in the bottom 20% (adj OR 1.47, 95% CI 1.33-1.62; p<0.001). The magnitude of risk for PAD conferred by high GRS was similar to many established clinical risk factors (Figure). A total of 91 ALI events occurred over a median follow-up of 2.4 years. Pts in the top 20% of GRS were at 63% increased risk for ALI compared with those in the bottom 80% (adj HR 1.63, 95% CI 1.04-2.56.; p=0.03), consistent in those with and without PAD (p-interaction 0.85). The PAD GRS was also associated with incident MI (n=2323), with pts in the top 20% of GRS at 42% increased risk compared with the bottom 80% (adj HR 1.42, 95% CI 1.36-1.49; p<0.001). Conclusions: A 19-SNP GRS was a strong independent predictor of PAD and ALI in patients with cardiometabolic disease. The PAD GRS also predicted MI, supporting overlapping biological mechanisms for atherosclerosis across vascular beds.
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