Polygenic prediction of coronary artery disease among 130,000 Mexican adults
Authors: Liu T , Friedrichs L G , Torres J , Baca P , Gonzalez-Carballo C , Ramirez-Reyes R , Rivas F , Aguilar-Ramirez D , Trichia E , Collins R , Emberson J , Alegre-Diaz J , Berumen J , Kuri-Morales P , Tapia-Conyer R 
Published: October 2024

Abstract

Background
Coronary artery disease (CAD) is a leading cause of premature mortality globally. Polygenic risk scores (PRSs) have been reported to enhance CAD prediction in populations of European ancestry but evidence from other populations is limited. We assessed the transferability and relevance of eight different external PRSs to the odds of premature CAD in a Mexican population with high levels of relatedness and ancestry admixture.

Methods
128,388 genotyped participants aged 35-74 years who were recruited between 1998 and 2004 into the Mexico City Prospective Study (MCPS) were included. We selected and recreated eight previously-reported CAD PRSs. The number of single nucleotide polymorphism variants included in the PRSs varied from 44 to 6,472,620. Premature CAD was defined as either self-reported history of heart attack or angina at recruitment or death before age 75 with CAD recorded on the death certificate. Age and sex-adjusted logistic regression was used to estimate the ability of each PRS to predict CAD, both overall and separately by age, sex and estimated proportion of Indigenous American ancestry. Analyses were repeated after further adjustment for conventional risk factors (blood pressure, adiposity, smoking, diabetes and highest education achieved). Risk discrimination was assessed using C-statistic.

Results
Of the 128,388 participants, 68% were women, mean (SD) age was 50.2±10.9 years and the average proportion of Indigenous American ancestry was 67%. CAD was identified for 3,871 (3.0%) participants; prior CAD was reported by 1,669 (1.3%) participants while 2,360 (1.8%) participants died before age 75 years with CAD mentioned on the death certificate. All eight PRSs were positively and approximately log-linearly associated with the odds of CAD, but the strength of association varied between the PRSs, ranging from a 7% increase per 1SD higher PRS (odds ratio [OR] 1.07, 95% CI 1.04-1.11) to a 33% increase (OR 1.33, 95% CI 1.29-1.37). Collectively, age, sex and (any) PRS resulted in a C-statistic of 0.70-0.71. C-statistics were slightly lower among those with a higher proportion of indigenous American ancestry. For four of the eight PRSs (including three of the four multi-ancestry PRSs) the increase in odds of CAD per 1SD higher PRS was significantly greater for men than women (eg, for the PRS with the strongest overall association with CAD the OR per 1SD higher PRS was 1.43 [95% CI 1.36-1.49] in men and 1.25 [1.20-1.31] in women). Further inclusion of conventional vascular risk factors reduced the strengths of associations of each PRS with CAD only slightly but increased the model C statistic to 0.74 in all cases.

Conclusions
In this population of admixed Mexican adults, existing PRSs predicted CAD reasonably well and independently of conventional vascular risk factors. Ancestry-specific instruments that more closely represent genetic variation in Mexico may further enhance polygenic prediction of CAD risk.Table 1.Baseline characteristicsFigure 1.Main analysis results