Abstract
BACKGROUND: We investigated the extent to which differences in coronary heart disease (CHD) risk between self-identified race/ethnicity (SIRE) groups are mediated by genetic, socio-environmental, and lifestyle factors. METHODS: In UK Biobank, we estimated genetic susceptibility for CHD using a polygenic risk score (PRS(CHD)) based on 1.7 million single-nucleotide variants (PGS Catalog identification: PGS000018), and socio-environmental-lifestyle risk for CHD using a polysocial risk score (PSS(CHD)) based on 100 covariates. Using SIRE, participants were grouped as White or non-White (Asian/Asian British, Black/Black British, and Chinese). Incident CHD was defined as a composite of fatal and non-fatal myocardial infarction and coronary revascularization. Multivariable Cox regression and mediation analyses were performed. RESULTS: Of 382,475 participants (55.6 ± 8.1 years, 57.5 % female, 94.9 % White, 1.7 % Asian/Asian British, 1.6 % Black/Black British, and 0.3 % Chinese), 9679 (2.5 %) had an incident CHD event, during 10 years of follow-up. The adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) for a 1 SD increase in PSS(CHD), and PRS(CHD) for CHD risk were 1.32 (1.30 to 1.35, P < 2 × 10(-16)), and 1.51 (1.48 to 1.55, P < 2 × 10(-16)), respectively. Asian/Asian British participants had the highest cumulative incidence of CHD, followed by White, Black/Black British and Chinese participants. The adjusted HR for the risk of incident CHD in non-Whites was 1.33 (95 % CIs: 1.20 to 1.48, P = 1.0 × 10(-7)); 44 % (95 % CIs: 37 to 73 %, P < 2 × 10⁻¹⁶) of the association of non-White SIRE with incident CHD was mediated through PSS(CHD) whereas PRS(CHD) mediated 33 % (95 % CIs: 22 to 43 %, P < 2 × 10⁻¹⁶) of the association. In subgroup analyses, non-Whites had higher socio-environmental and lifestyle risk than Whites, while Asian/Asian British had the highest genetic susceptibility for CHD, followed by White, Black/Black British and Chinese individuals. CONCLUSIONS: Socio-environmental and lifestyle factors had a stronger mediating effect than genetic factors on the association between SIRE and CHD in the UK Biobank. These findings advance our understanding of factors underlying differences in CHD risk across SIRE groups.