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| Naji, M. |
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| Motta, Antonella |
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| Mohamed, Tarek |
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| Ertürk, Emre |
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| Taccardi, Nicola |
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| Petrov, R. H. | Madrid |
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| Alshaaer, Mazen | Brussels |
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| Bih, L. |
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| Casati, R. |
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| Kočí, Jan | Prague |
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| Šuljagić, Marija |
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| Kalteremidou, Kalliopi-Artemi | Brussels |
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| Azam, Siraj |
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| Ospanova, Alyiya |
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| Ali, M. A. |
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| Popa, V. |
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| Rančić, M. |
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| Ollier, Nadège |
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| Azevedo, Nuno Monteiro |
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| Landes, Michael |
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Radic Savic, Z.
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article
<i>GPX3</i> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy.
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. <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.