A genetic risk score is associated with increased coronary plaque burden but not specific plaque features: a coronary computed tomography study

Background Genetic risk scores (GRSs) based on risk variants identified from genome-wide association studies (GWASs) predict coronary artery disease (CAD) risk. However, it is unknown whether the GRS is associated with coronary plaque burden or specific high-risk plaque features responsible for the clinical disease onset. Purpose To investigate if a GRS is associated with coronary plaque burden and specific plaque characteristics, in patients with suspected stable CAD referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing coronary CTA. Using LDPred, a previously validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Plaques were evaluated using an 18-segment model and characterized by stenosis severity (0%, 1-49%, 50-69%, 70-100%) and composition (calcified (>80% calcified), mixed-calcified (50-80% calcified), mixed-soft (20-50% calcified), or soft (<20% calcified)). The segment stenosis score and the coronary artery calcium score (CACS) were used as measures of plaque burden. Multivariate regression models were used to assess the effect per standard deviation (SD) of the GRS with adjustment for age, sex, hypertension, hypercholesterolemia, BMI, chest pain symptoms, and active smoking. Results For each SD increase in the GRS, the segment stenosis score increased with 49% (p=8.6e-27) and CACS increased with 110% (p=2.3e-24). The GRS was associated with a higher risk of plaque stenosis >50% (OR: 1.74, p=3.2e-15), calcified (OR: 1.65, p=3.0e-16), mixed-calcified (OR: 1.64, p=1.5e-8), mixed-soft (OR: 1.44, p=1.6e-6), and soft plaques (OR: 1.40, p=3.0e-6), and all coronary vessels were more often affected with plaques (all p-values <1.0e-4). When analyzing the plaque characteristics (3007 plaques in 849 patients), the GRS was associated with stenosis severity (OR per severity category: 1.15 (p=0.005), but not with extent of calcification, proximal location, or presence in any of the major coronary vessels (all p-values >0.05). Conclusion The GRS was strongly associated with the extent and severity of CAD at coronary CTA, but not any specific plaque characteristics per se. The results may suggest that polygenic risk based on large CAD-GWAS increases CAD risk through increased coronary plaque burden rather than specific plaque features.