Abstract: 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.
