Abstract
Abstract only Introduction: Saudi Arabia is the largest country in the Middle East and has an alarming rise in cardiometabolic disease. While conventional risk factors are highly prevalent, it is not clear if and how genomic risk might be playing a role. Methods: In 5,399 Saudi patients (age 54.8±14.8 years, 35.7% female) referred for cardiac catheterization, we collected detailed cardiometabolic phenotype data and performed whole-genome genotyping. We implemented a computational framework to develop Arab-specific polygenic scores for 9 traits (Figure A, B). We studied the association of the polygenic scores with cardiometabolic disease, and their interplay with conventional risk factors using regression models adjusted for age, sex, and genetic ancestry. Results: Within this disease cohort with high prevalence of conventional risk factors - 65.0% coronary artery disease (CAD), 55.6% type 2 diabetes (DM-2), 41.5% obesity, 48.8% hypercholesterolemia, 80.6% hypertension, and 38.3% smoking - polygenic scores were strongly associated with cardiometabolic traits (Figure C). The effect sizes of polygenic scores for CAD and DM-2 remained unchanged with adjustment for clinical risk factors. Genomic risk was also associated with the severity of CAD, as measured by the number of vessels with severe stenosis on cardiac catheterization (Figure D). CAD patients with high genomic risk - defined as top quintile of the polygenic score - (N=568) had earlier onset (54.8 vs. 57.9 years, p=0.001) and more severe disease (41.3% vs. 29.9% with three-vessel CAD, p<0.001) despite similar clinical risk factors, compared to CAD patients without high genomic risk (N=1144). Conclusions: Polygenic scores were strongly associated with cardiometabolic disease even in a non-European population with high prevalence of conventional risk factors. Genomic risk for CAD appears independent of conventional risk factors and identifies patients with earlier onset and more severe disease.