Abstract

The base excision repair (BER) pathway, containing OGG1, MTH1 and MUTYH, is a major protector from oxidative DNA damage in humans, while 8-oxoguanine (8-OHdG), an index of DNA oxidation, is increased in maintenance hemodialysis (HD) patients. Four polymorphisms of BER genes, OGG1 c.977C > G (rs1052133), MTH1 c.247G > A (rs4866), MUTYH c.972G > C (rs3219489), and AluYb8MUTYH (rs10527342), were examined in 337 HD patients and 404 healthy controls. And the 8-OHdG levels in leukocyte DNA were examined in 116 HD patients. The distribution of MUTYH c.972 GG or AluYb8MUTYH differed between the two groups and was associated with a moderately increased risk for end-stage renal disease (ESRD) (P = 0.013 and 0.034, resp.). The average 8-OHdG/106 dG value was significantly higher in patients with the OGG1 c.977G, MUTYH c.972G or AluYb8MUTYH alleles (P < 0.001 via ANOVA). Further analysis showed that combination of MUTYH c.972GG with OGG1 c.977GG or AluYb8MUTYH increased both the risk for ESRD and leukocyte DNA 8-OHdG levels in HD patients. Our study showed that MUTYH c.972GG, AluYb8MUTYH, and combination of OGG1 c.977GG increased the risk for ESRD development in China and suggested that DNA oxidative damage might be involved in such process.

Highlights

  • Oxidative stress is characterized by an excess of reactive oxygen species (ROS) and leads to cellular injury via reactions with proteins, nucleic acids, and lipids [1, 2]

  • Our study showed that MUTYH c.972GG, AluYb8MUTYH, and combination of OGG1 c.977GG increased the risk for end-stage renal disease (ESRD) development in China and suggested that DNA oxidative damage might be involved in such process

  • Several repair pathways are involved with the DNA insults that result from either endogenous sources or exogenous sources, including the direct reversal pathway, the mismatch repair (MMR) pathway, the nucleotide excision repair (NER) pathway, and the base excision repair (BER)

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Summary

Introduction

Oxidative stress is characterized by an excess of reactive oxygen species (ROS) and leads to cellular injury via reactions with proteins, nucleic acids, and lipids [1, 2]. The BER pathway prevents those G : C-toT : A mutations by the repair of 8-OHdG It includes the MTH1, OGG1, and MUTYH genes that prevent, recognize and remove the misincorporated oxidized nucleotide, 8OHdG, and the adenine paired with 8-OHdG, respectively, when initiated by the BER pathway. Based on the association of BER polymorphisms, oxidative DNA damages, and ESRD, we hypothesized that genetic variation in the BER genes might lead to repair impairment or disability, oxidative DNA damage accumulation, and pathogenesis of ESRD. Given the potential roles of OGG1 c.977C > G, MTH1 c.247G > A, MUTYH c.972G > C, and AluYb8MUTYH in the oxidative DNA repair pathway; we examined the association between these four polymorphisms in the BER pathway and ESRD in a Chinese cohort. We assessed the leukocyte DNA 8-OHdG levels in HD patients to reveal the correlation between oxidative damage and endstage renal disease arises

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