부산대학교 도서관

Introduction. We assessed the effects of a polygenic risk score (PRS), monogenic variants (Mono), and family history (FamHx) on the risk of coronary heart disease (CHD) and whether incorporating a PRS into the Pooled Cohort Equations (PCE) improves risk prediction.Method. In 199,997 UK Biobank participants, we calculated a PRSCHD (metaGRS, based on ~1.6 million single nucleotide variants), identified individuals with monogenic etiology (presence of a pathogenic variant in LDLR, APOB, or PCSK9), and ascertained family history of CHD (CHD in a first-degree relative). Odds of CHD (myocardial infarction/ coronary revascularization/ cardiovascular death) associated with PRSCHD, Mono, and FamHx at age 55 were computed using logistic regression analyses adjusted for age, sex, and first 4 principal components of ancestry. We combined PRSCHD and PCE into an integrated score (IS) and assessed net reclassification using an actionable risk threshold of 7.5%.Results. The odds ratio (OR) for CHD in the top 5 percentile of PRSCHD (PRSP95), Mono, and FamHx were 3.37 (2.98 - 3.81), 2.68 (1.67 - 4.07), and 1.61 (1.47 - 1.76), respectively (all p<0.001). These effects were independent and similar in different subgroups. (Figure 1-A) Compared to PRSQ2-4Mono (3 middle quintiles of PRSCHD and no monogenic variants), the OR for CHD ranged from 1.73 (0.28 - 5.48, p = 0.446) in PRSQ1Mono to 5.10 (2.14 - 10.24, p <0.001) in PRSQ5Mono. A similar pattern was seen for other combinations, indicating additive effects (Figure 1-B). Incorporating PRSCHD into PCE resulted in a net reclassification improvement of 4.56%. Compared to those with high PCE and low IS, the hazard ratio for CHD in those with low PCE and high IS was 1.48 (1.34 - 1.64, p <0.001).Conclusion. The CHD risk associated with PRSCHD, monogenic variants, and family history is independent and additive. Combining PRSCHD and PCE improved risk prediction, that could improve further by adding monogenic variants and family history.