<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...
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MDPI AG
2023-08-01
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| Online Access: | https://www.mdpi.com/1648-9144/59/8/1421 |
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| author | Zana Radic Savic Vesna Coric Stojko Vidovic Vanja Vidovic Jelena Becarevic Irina Milovac Zorica Reljic Bosa Mirjanic-Azaric Ranko Skrbic Radoslav Gajanin Marija Matic Tatjana Simic |
| author_facet | Zana Radic Savic Vesna Coric Stojko Vidovic Vanja Vidovic Jelena Becarevic Irina Milovac Zorica Reljic Bosa Mirjanic-Azaric Ranko Skrbic Radoslav Gajanin Marija Matic Tatjana Simic |
| author_sort | Zana Radic Savic |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T23:45:45Z |
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| spelling | doaj.art-8b41fa6ceab545288bfc7539fed6563a2023-11-19T02:06:01ZengMDPI AGMedicina1010-660X1648-91442023-08-01598142110.3390/medicina59081421<em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic NephropathyZana Radic Savic0Vesna Coric1Stojko Vidovic2Vanja Vidovic3Jelena Becarevic4Irina Milovac5Zorica Reljic6Bosa Mirjanic-Azaric7Ranko Skrbic8Radoslav Gajanin9Marija Matic10Tatjana Simic11Department of Medical Biochemistry, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaInstitute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaCentre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaCentre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaCentre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaCentre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaMedical Laboratory “PAN LAB”, 36000 Kraljevo, SerbiaDepartment of Medical Biochemistry, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaDepartment of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaDepartment of Pathological Anatomy, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Bosnia and HerzegovinaInstitute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaInstitute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, SerbiaCurrent 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.https://www.mdpi.com/1648-9144/59/8/1421Balkan endemic nephropathyupper tract urothelial cell carcinomaaristolochic acid<i>GPX3</i> polymorphism |
| spellingShingle | Zana Radic Savic Vesna Coric Stojko Vidovic Vanja Vidovic Jelena Becarevic Irina Milovac Zorica Reljic Bosa Mirjanic-Azaric Ranko Skrbic Radoslav Gajanin Marija Matic Tatjana Simic <em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy Medicina Balkan endemic nephropathy upper tract urothelial cell carcinoma aristolochic acid <i>GPX3</i> polymorphism |
| title | <em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy |
| title_full | <em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy |
| title_fullStr | <em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy |
| title_full_unstemmed | <em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy |
| title_short | <em>GPX3</em> rs8177412 Polymorphism Modifies Risk of Upper Urothelial Tumors in Patients with Balkan Endemic Nephropathy |
| title_sort | em gpx3 em rs8177412 polymorphism modifies risk of upper urothelial tumors in patients with balkan endemic nephropathy |
| topic | Balkan endemic nephropathy upper tract urothelial cell carcinoma aristolochic acid <i>GPX3</i> polymorphism |
| url | https://www.mdpi.com/1648-9144/59/8/1421 |
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