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Research Article: Several antiplatelet gene SNPs, their haplotypes and G × E interactions on premature coronary artery disease

Date Published: 2026-06-29

Abstract:
To investigate the impact of single nucleotide polymorphisms (SNPs) and haplotypes of antiplatelet drug metabolism-related genes— CYP2C19 , PTGS1 , ITGB3 , PEAR1 , and GP1BA —as well as their gene-gene ( G × G ) and gene-environment ( G × E ) interactions on the risk of premature coronary artery disease (PCAD). This real-world study enrolled 1,108 participants, including PCAD patients and angiography-referred controls without obstructive CAD. Twelve SNP loci were genotyped using PCR amplification followed by digoxigenin-based colorimetric detection, including CYP2C19 (rs4244285, rs12248560, rs12769205, rs3758580, rs4917623), PTGS1 (rs1330344, rs3842788, rs5788), ITGB3 (rs5918), PEAR1 (rs12041331) , and GP1BA (rs6065 and rs2243093). Linkage disequilibrium and population-level haplotype frequencies were assessed using Haploview software, and haplotype carrier status used in regression analyses was inferred from haplotype probability outputs. The generalized multifactor dimensionality reduction (GMDR) method was employed to identify G × G and G × E interaction models, and logistic regression was used to evaluate their combined effects. Significant differences in genotype and allele frequencies between PCAD patients and controls were observed for rs12769205, rs3758580, rs4917623 and rs1330344 ( P <?0.05). The dominant model of rs12769205 exhibited a protective effect, whereas the dominant models of rs3758580, rs4917623, and rs1330344 were associated with increased PCAD risk ( P <?0.05). Haplotype analysis showed that CYP2C19 G-C-C-A-A and CYP2C19 G-C-C-C-C were protective, while CYP2C19 G-C-A-A-A , G-C-A-C-C , A-C-C-A-A , PTGS1 C-A-A , C-A-C , and ITGB3-GP1BA A-C-C increased PCAD risk ( P <?0.05). GMDR analysis identified significant interaction models. For SNP-SNP interactions, individuals carrying the rs12769205 AC/CC genotype combined with the rs3758580 CC genotype (OR?=?0.76, 95% CI: 0.55–0.96, P <?0.05), rs12769205 AC/CC genotype without diabetes mellitus (DM) (OR?=?0.55, 95% CI: 0.21–0.88, P <?0.05), CYP2C19-C2 (G-C-C-A-A) carriers without ITGB3-GP1BA-A2 (A-C-C) carriage (OR?=?0.64, 95% CI: 0.58–0.89, P <?0.05), and CYP2C19-C2 carriers without DM (OR?=?0.77, 95% CI: 0.54–0.96, P <?0.05) exhibited the lowest PCAD risk. These interaction findings should be interpreted cautiously because they were not externally replicated. Polymorphisms, haplotypes and interactions of antiplatelet drug-related genes significantly influence the risk of PCAD. Environmental exposures should be considered in early warning and individualized prevention of PCAD.

Introduction:
Coronary artery disease (CAD) is a cardiac disorder caused by myocardial ischemia, hypoxia, or necrosis resulting from luminal narrowing or occlusion due to coronary atherosclerosis. It remains one of the leading causes of disability and mortality worldwide ( 1 ). According to the 2023 China Cardiovascular Health and Disease Report, there are currently approximately 330 million patients with cardiovascular disease in China, including 245 million with hypertension, 13 million with stroke, 11.39 million with CAD,…

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