Background: Genome-wide association studies (GWAS) have identified more than 320 risk loci for coronary artery disease (CAD). While the assessment of an individual’s genetic risk might improve cardiovascular risk prediction, the association between higher genetic risk and distinct histopathologic characteristics of CAD remain unclear.

Methods: From 4,327 subjects referred to our institute by the State of Maryland Office Chief Medical Examiner (OCME) for sudden death between 1994 and 2015, 2,455 cases were randomly selected for genotyping. From 321 common CAD risk loci with genome-wide significance, 238 were available in our dataset and used to calculate a polygenic risk score (PRS). Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including plaque burden, calcification, thin-cap fibroatheromas, and thrombotic CAD, as well as CAD-associated cause of death.

Results: After exclusion of cases with insufficient DNA sample quality or with inconsistent data, 954 cases (mean age 48.82±14.65; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared to subjects in the lowest quintile, with greater mean cross-sectional luminal narrowing (80.0% (95%CI, 76.2%-83.9%) vs. 51.1% (95%CI, 45.5%-56.7%); adjusted p<0.001). Higher z-score-standardized PRS was associated with unstable plaque features, including thin-cap fibroatheroma (adjusted OR 1.48; 95%CI 1.20-1.83; adjusted p<0.001) and calcification (adjusted OR 1.32; 95%CI 1.10-1.57; adjusted p=0.002) even after additional controlling for traditional CAD risk factors. Higher PRS was also associated with plaque rupture (adjusted OR 1.54; 95% CI 1.30-1.83; adjusted p<0.001) and predicted CAD-associated cause of death among subjects younger than 50 years of age (adjusted OR 1.53; 95%CI 1.23-1.89; p<0.001), but not among subjects of 50 years and older. No associations were detected for higher PRS and plaque erosion, however, individual SNPs showed distinct associations with plaque rupture and erosion.

Conclusion: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at a histopathologic level. Our pathological analysis suggests PRS correlates with atherosclerosis severity and instability and may be useful as a method for CAD risk stratification, especially in younger subjects. Analysis of individual CAD risk loci and related pathophysiological pathways may be an avenue towards a better understanding of the mechanisms by which genetics have impact on atherosclerosis.

Figure 1 – Associations with plaque burden. The maximum percentage of cross-sectional luminal narrowing (i.e., max. %stenosis) was on average significantly higher in subjects within the highest PRS quintile compared to the lowest quintile.

Figure 2 – Associations with histopathologic plaque features. While a higher PRS was observed in subjects with calcified plaques, thin-cap fibroatheromas and plaque rupture as compared to subjects without these features, no such difference was observed in plaque erosion.