Association of <i>Nrf2</i>, <i>SOD2</i> and <i>GPX1</i> Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients

• Main Authors: Djurdja Jerotic, Marija Matic, Sonja Suvakov, Katarina Vucicevic, Tatjana Damjanovic, Ana Savic-Radojevic, Marija Pljesa-Ercegovac, Vesna Coric, Aleksandra Stefanovic, Jasmina Ivanisevic, Zorana Jelic-Ivanovic, Lana McClements, Nada Dimkovic, Tatjana Simic
• Format: Article
• Language: English
• Published: MDPI AG 2019-07-01
• Series: Toxins
• Subjects: end-stage renal disease; hemodialysis; survival; Nrf2; SOD2; GPX1; polymorphism; oxidative stress
• Online Access: https://www.mdpi.com/2072-6651/11/7/431

The oxidative stress response via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) interlinks inflammation- and metabolism-related pathways in chronic kidney disease. We assessed the association between polymorphisms in Nrf2, superoxide dismutase (SOD2), glutathione peroxidase (GPX1), and the risk of end-stage renal disease (ESRD). The modifying effect of these polymorphisms on both oxidative phenotype and ESRD prognosis, both independently and/or in combination with the glutathione S-transferase M1 (<i>GSTM1</i>) deletion polymorphism, was further analyzed. Polymorphisms in <i>Nrf2</i> (rs6721961), <i>SOD2</i> (rs4880), <i>GPX1</i> (rs1050450), and <i>GSTM1</i> were determined by PCR in 256 ESRD patients undergoing hemodialysis and 374 controls. Byproducts of oxidative stress were analyzed spectrophotometically or by ELISA. Time-to-event modeling was performed to evaluate overall survival and cardiovascular survival. The <i>SOD2 Val</i>/<i>Val</i> genotype increased ESRD risk (OR = 2.01, <i>p</i> = 0.002), which was even higher in combination with the <i>GPX1 Leu/Leu</i> genotype (OR = 3.27, <i>p</i> = 0.019). Polymorphism in <i>SOD2</i> also showed an effect on oxidative phenotypes. Overall survival in ESRD patients was dependent on a combination of the <i>Nrf2</i> (<i>C</i>/<i>C</i>) and <i>GPX1 (Leu</i>/<i>Leu)</i> genotypes in addition to a patients&#8217; age and <i>GSTM1</i> polymorphism. Similarly, the <i>GPX1 (Leu</i>/<i>Leu)</i> genotype contributed to longer cardiovascular survival. Conclusions: Our results show that <i>SOD2</i>, <i>GPX1</i>, and <i>Nrf2</i> polymorphisms are associated with ESRD development and can predict survival.