The GPX3 rs3828599 genotype in combination with alcohol consumption and age helps identify a high-risk hypertension subgroup for antioxidant intervention

Essential hypertension involves complex gene–environment interactions. Identifying high-risk subgroups for targeted intervention remains a challenge in hypertension prevention. We hypothesized that integrating the GPX3 rs3828599 polymorphism with environmental risk factors could stratify individuals to warrant precision antioxidant-based prevention. In a rural Han Chinese case‒control investigation involving 400 hypertensive patients and 400 normotensive controls, we conducted genotyping of the GPX3 promoter variant rs3828599, measured the serum levels of GPx-3, and evaluated the interactions between GPx-3 and metabolic and lifestyle factors. Multivariable logistic regression was employed to assess the risk of hypertension under genetic models, while gene‒environment interactions were analysed using MDR. The rs3828599 C allele was found to significantly increase the risk of hypertension. In the codominant model, when the CC genotype was compared with the TT genotype, the odds ratio (OR) was 2.12 (95% CI: 1.38–3.24; P = 0.001), indicating an allele-dose effect, with the risk increasing in the order TT < TC < CC. The serum level of GPx-3 was significantly lower in hypertensive patients (P < 0.001) and displayed a genotype-dependent gradient in the order TT > TC > CC (P < 0.001). Serum GPx-3 levels were inversely correlated with systolic blood pressure (β=−0.424; P < 0.001) and diastolic blood pressure (β=−0.179; P < 0.001) but positively correlated with HDL-C levels (β = 0.129; P < 0.001). MDR analysis revealed a crucial three-way interaction: individuals who carried the rs3828599 TC/CC genotype and consumed alcohol and were of advanced age (men > 50 years or women > 65 years) had a 4.7-fold increased risk of hypertension (OR = 4.7, 95% CI: 1.827–12.092; P < 0.001). The combination of the GPX3 rs3828599 TC/CC genotype, alcohol use, and advanced age defines a high-risk hypertension subgroup with increased oxidative stress. This precision stratification model enables targeting of antioxidant interventions to mitigate excess risk in susceptible populations.