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Background 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. Methods 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. Results 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). Conclusions 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.

Current data suggest that aristolochic acid (AA) exposure is a putative cause of Balkan endemic nephropathy (BEN), a chronic kidney disease strongly associated with upper tract urothelial carcinoma. The cellular metabolism of AA is associated with the production of reactive oxygen species, resulting in oxidative distress. Purpose: Therefore, the aim of this study was to analyze individual, combined and cumulative effect of antioxidant gene polymorphisms (Nrf2 rs6721961, KEAP1 rs1048290, GSTP1AB rs1695, GSTP1CD rs1138272, GPX3 rs8177412 and MDR1 rs1045642), as well as GSTP1ABCD haplotypes with the risk for BEN development and associated urothelial cell carcinoma in 209 BEN patients and 140 controls from endemic areas. Experimental method: Genotyping was performed using polymerase chain reaction (PCR) and PCR with confronting two-pair primers (PCR-CTTP) methods. Results: We found that female patients carrying both variant GPX3 rs8177412 and MDR1 rs1045642 genotypes in combination exhibited significant risk towards BEN (OR 1 = 3.34, 95% CI = 1.16–9.60, p = 0.025; OR 2 = 3.79, 95% CI = 1.27–11.24, p = 0.016). Moreover, significant association was determined between GPX3rs8174412 polymorphism and risk for urothelial carcinoma. Carriers of variant GPX3*TC + CC genotype were at eight-fold increased risk of BEN-associated urothelial tumors development. There was no individual or combined impact on BEN development and BEN-associated tumors among all examined polymorphisms. The haplotype consisting of variant alleles for both polymorphisms G and T was associated with 1.6-fold increased risk although statistically insignificant (OR = 1.64; 95% CI = 0.75–3.58; p = 0.21). Conclusions: Regarding GPX3 rs8177412 polymorphism, the gene variant that confers lower expression is associated with significant increase in upper urothelial carcinoma risk. Therefore, BEN patients carrying variant GPX3 genotype should be more frequently monitored for possible upper tract urothelial carcinoma development.

Although disturbance of redox homeostasis might be responsible for COVID-19 cardiac complications, this molecular mechanism has not been addressed yet. We have proposed modifying the effects of antioxidant proteins polymorphisms (superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3) and nuclear factor erythroid 2-related factor 2, (Nrf2)) in individual susceptibility towards the development of cardiac manifestations of long COVID-19. The presence of subclinical cardiac dysfunction was assessed via echocardiography and cardiac magnetic resonance imaging in 174 convalescent COVID-19 patients. SOD2, GPX1, GPX3 and Nrf2 polymorphisms were determined via the appropriate PCR methods. No significant association of the investigated polymorphisms with the risk of arrhythmia development was found. However, the carriers of variant GPX1*T, GPX3*C or Nrf2*A alleles were more than twice less prone for dyspnea development in comparison with the carriers of the referent ones. These findings were even more potentiated in the carriers of any two variant alleles of these genes (OR = 0.273, and p = 0.016). The variant GPX alleles were significantly associated with left atrial and right ventricular echocardiographic parameters, specifically LAVI, RFAC and RV-EF (p = 0.025, p = 0.009, and p = 0.007, respectively). Based on the relation between the variant SOD2*T allele and higher levels of LV echocardiographic parameters, EDD, LVMI and GLS, as well as troponin T (p = 0.038), it can be proposed that recovered COVID-19 patients, who are the carriers of this genetic variant, might have subtle left ventricular systolic dysfunction. No significant association between the investigated polymorphisms and cardiac disfunction was observed when cardiac magnetic resonance imaging was performed. Our results on the association between antioxidant genetic variants and long COVID cardiological manifestations highlight the involvement of genetic propensity in both acute and long COVID clinical manifestations.