Ethnicity-specific polygenic risk score for predicting coronary heart disease mortality in Malaysian patients with...

Polygenic risk scores (PRS) are used to aggregate single-nucleotide polymorphisms (SNPs) effects across the genome to estimate an individual's risk of coronary heart disease (CHD). However, most PRS models were developed mainly in Caucasian populations, limiting their applicability to Malaysia's diverse populations. This study aimed to develop a PRS to predict CHD mortality among individuals with type 2 diabetes (T2D) in The Malaysian Cohort (TMC).

In Phase 1, 224 CHD-death cases and 625 controls were genotyped using Illumina's Infinium Asian Screening Array, followed by genetic imputation. From the genome-wide association analysis, 56 SNPs were identified at suggestive genome-wide significance (P < 5 × 10-⁵), with 15 SNPs selected to construct the PRS. In Phase 2, 806 T2D participants without known CHD at baseline were followed until death.

The PRS distinguished cases from controls across all ethnicities, with an area under the receiver operating characteristic curve (AUC) indicating good discriminative ability. At 0.85 cut-off score, the PRS achieved 64.7% sensitivity and 73.1% specificity. Those in the high-PRS category had significantly shorter mean survival than those in the low-risk group: observed among Malays (6.60 vs 8.92 years), Chinese (6.20 vs 8.66 years), and Indians (7.21 vs 8.60 years). After adjusting for covariates, high-PRS individuals had increased CHD mortality risk, with hazard ratios of 3.23 (Malays), 9.59 (Chinese), and 9.65 (Indians) (all p<0.05).

This study demonstrates the utility of a population-specific PRS in predicting CHD mortality among Malaysian T2D patients, supporting its potential role in precision medicine and long-term risk stratification.