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ABSTRACT

Aim Most polygenic risk scores (PRSs) for coronary heart disease (CHD) were derived from European ancestry populations. This paper evaluates the performance of CHD PRSs in a Mexican population. Methods 133,207 participants aged 35-79 years from the Mexico City Prospective Study were included. Eight PRSs (comprising 44 to 6,472,620 polymorphisms) were selected for prediction of CHD (defined as self-reported prior heart attack or angina, or CHD death before age 80 years). Logistic regression was adjusted for age, sex, and the seven genetic principal components, before and after adjustment for other cardiovascular risk factors. The area under the receiving operating characteristic curve (“C-statistic”) was also estimated. Results Of the participants, 67% were women, the mean (±SD) age was 51±12 years, and Indigenous American ancestry averaged 67%. CHD was documented for 5,163 participants (3.9%), including 1,901 prevalent and 3,479 fatal cases. All eight PRSs were positively and log-linearly associated with CHD, with odds ratios (ORs) per 1 SD PRS increase ranging from 1.05 (95% CI, 1.03–1.08) to 1.29 (95% CI, 1.25–1.33). Associations were consistent across strata of age and ancestry, and were independent of other vascular risk factors. For six PRSs, however, associations were substantially stronger in men than women. Multi-ancestry PRSs outperformed Eurocentric-ancestry PRSs. Despite remaining predictive of risk independently of established non-genetic risk factors, inclusion of a PRS into a risk model did not increase the C-statistic noticeably. Conclusions In this Mexican population, existing PRSs predicted CHD independently of established vascular risk factors, particularly for men. PRSs better capturing genetic variation in Latin American people may further enhance risk prediction in such populations.

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