<em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy
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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-08-01
|
| Series: | Medicina |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1648-9144/59/8/1421 |
| Summary: | 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. <i>Purpose:</i> Therefore, the aim of this study was to analyze individual, combined and cumulative effect of antioxidant gene polymorphisms (<i>Nrf2</i> rs6721961, <i>KEAP1</i> rs1048290, <i>GSTP1AB</i> rs1695, <i>GSTP1CD</i> rs1138272, <i>GPX3</i> rs8177412 and <i>MDR1</i> rs1045642), as well as <i>GSTP1ABCD</i> haplotypes with the risk for BEN development and associated urothelial cell carcinoma in 209 BEN patients and 140 controls from endemic areas. <i>Experimental method:</i> Genotyping was performed using polymerase chain reaction (PCR) and PCR with confronting two-pair primers (PCR-CTTP) methods. <i>Results:</i> We found that female patients carrying both variant <i>GPX3</i> rs8177412 and <i>MDR1</i> rs1045642 genotypes in combination exhibited significant risk towards BEN (OR 1 = 3.34, 95% CI = 1.16–9.60, <i>p</i> = 0.025; OR 2 = 3.79, 95% CI = 1.27–11.24, <i>p</i> = 0.016). Moreover, significant association was determined between <i>GPX3</i>rs8174412 polymorphism and risk for urothelial carcinoma. Carriers of variant <i>GPX3</i>*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; <i>p</i> = 0.21). <i>Conclusions:</i> Regarding <i>GPX3</i> rs8177412 polymorphism, the gene variant that confers lower expression is associated with significant increase in upper urothelial carcinoma risk. Therefore, BEN patients carrying variant <i>GPX3</i> genotype should be more frequently monitored for possible upper tract urothelial carcinoma development. |
|---|---|
| ISSN: | 1010-660X 1648-9144 |