Abstract 10360: Polygenic Risk Score, Rare Monogenic Variants, and Family History Have Independent and Additive Effects on the Risk of Coronary Heart Disease

• Published in: Circulation (New York, N.Y.) N.Y.), 2022-11, Vol.146 (Suppl_1), p.A10360-A10360
• Main Authors: Saadatagah, Seyedmohammad, Hamed, Marwan, Miller, Alexandra, Bangash, Hana, Nigbur, Scott, Kamzabek, Arailym, Norland, Kristjan, Kosel, Matt, Schaid, Daniel, Kullo, Iftikhar J
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.10360

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 5th 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