Genetics of Cholesterol and Coronary Disease Risk across Six Global Ancestries

Clinical trials of low-density lipoprotein cholesterol (LDL-C)-lowering medicines have shown improvement in cardiovascular disease risk. However, representation across diverse communities in such trials is limited. We set out to study whether or not more diverse human genetic studies could provide an opportunity to test whether these trial results can be generalized to poorly populations poorly represented in drug clinical trials.

We included six cohorts across 967,325 individuals (54.5% female), including 65,258 African, 45,393 admixed American, 179,521 East Asian, 616,045 European, 4686 Middle Eastern, and 56,422 South Asian individuals. Genetic ancestry was determined using genetic principal components and k-nearest neighbors. We constructed ancestry-specific LDL-C polygenic risk scores (PGS) using genome-wide association study (GWAS) summary statistics trained and externally validated on each ancestry. We associated each PGS with population LDL-C, scaled for a 40 mg/dl increase, and tested these scores against coronary artery disease (CAD) risk using hierarchical Bayesian meta-analyses.

The associations between genetically predicted LDL-C levels and observed LDL-C were consistent across ancestries, supporting the validity of our genetic proxy. When scaled to mimic a 40 mg/dl increase in LDL-C, the PGS showed positive but heterogeneous associations with CAD. Posterior odds ratios for CAD ranged from 1.35 (95% credible interval, 1.05 to 1.68) in African populations to 1.82 (95% credible interval, 1.33 to 2.97) in Middle Eastern populations. Bayesian analysis revealed that 97.9% of posterior samples showed all population means greater than 0 on a log scale with a between-ancestry posterior variance (τ²) of 0.062 (95% credible interval, 0.001 to 0.352).

Our findings demonstrated a consistent association between LDL-C and CAD risk across diverse ancestry groups that are often poorly represented in clinical trials, although effect magnitudes varied. (Funded by the National Institutes of Health and others.).