Genomic Drivers of Coronary Artery Disease and Risk of Future Outcomes After Coronary Angiography

Importance: Disease characteristics of genetically mediated coronary artery disease (CAD) on coronary angiography and the association of genomic risk with outcomes after coronary angiography are not well understood. Objective: To assess the angiographic characteristics and risk of post-coronary angiography outcomes of patients with genomic drivers of CAD: familial hypercholesterolemia (FH), high polygenic risk score (PRS), and clonal hematopoiesis of indeterminate potential (CHIP). Design, Setting, and Participants: A retrospective cohort study of 3518 Mass General Brigham Biobank participants with genomic information who underwent coronary angiography was conducted between July 18, 2000, and August 1, 2023. Exposures: The presence of a genomic risk factor of CAD, defined as FH variant, high CAD PRS, or CHIP driver variation. Main Outcomes and Measures: Coronary artery disease presentation (stable or acute), angiographic CAD characteristics (severity and burden), angiographic outcomes (repeat angiogram, revascularization, and in-stent restenosis), and clinical outcomes (heart failure and all-cause mortality). Results: Among 3518 participants (2467 [70.1%] male; median age, 64.0 [IQR, 55.0-72.0] years), 1509 (42.9%) had at least 1 genomic driver of CAD (26 FH, 1191 high CAD PRS, and 466 CHIP) that was associated with the presentation of acute coronary syndromes (adjusted odds ratio, 2.67; 95% CI, 2.19-3.26) and with the presence, burden, and severity of angiographic CAD. This association was driven by FH and CAD PRS. One SD of CAD PRS was associated with a 12.51-point higher Gensini score. During 9 years of follow-up, there was an increased risk among FH carriers for a repeat angiogram (adjusted hazard ratio [AHR], 1.70; 95% CI, 1.02-2.83), and revascularization (AHR, 1.97; 95% CI, 1.02-3.80), and among people with high CAD PRS (repeat angiogram: AHR, 1.79; 95% CI, 1.45-2.22; revascularization: AHR, 1.85; 95% CI, 1.37-2.50; and in-stent restenosis: AHR, 3.89; 95% CI, 2.16-7.01). CHIP carriers had no significant increase in angiographic outcomes but were at higher risk of heart failure (AHR, 1.58; 95% CI, 1.04-2.40) and all-cause mortality (AHR, 1.78; 95% CI, 1.47-2.16). Conclusions and Relevance: The findings of this study suggest that germline monogenic and polygenic risk are associated with acute coronary syndromes presentation, severity and burden of atherosclerosis, and risk of repeat angiogram, revascularization, and in-stent restenosis. CHIP variant status is associated with incident heart failure and mortality after coronary angiography.