Base excision repair gene polymorphisms are associated with inflammation in patients undergoing chronic hemodialysis

ArticleinBiochemical and Biophysical Research Communications 424(3):611-5 · July 2012with7 Reads
Impact Factor: 2.30 · DOI: 10.1016/j.bbrc.2012.06.161 · Source: PubMed

Chronic inflammation may increase the risk of mortality for patients undergoing hemodialysis, while enhanced oxidative stress and DNA oxidative damage are involved in the inflammatory response. The purpose of this study was to examine the associations between inflammation and polymorphisms in the base excision repair (BER) system, which protects against oxidative DNA damage, among hemodialysis patients. Data were analyzed from 167 hemodialysis patients and 66 healthy controls. All subjects were evaluated for the expression of inflammatory cytokines (IL-1β and IL-6) and genotyped for two BER genes, including hOGG1 c.977C>G, MUTYH c.972G>C and AluYb8MUTYH. The results showed that the hemodialysis patients had significantly higher levels of IL-1β and IL-6 than the healthy controls. In the healthy controls, no patterns of association were observed between the hOGG1 c.977C>G or MUTYH c.972G>C genotypes and IL-1β or IL-6 levels; however, patients with the MUTYH c.972G/G genotype presented higher levels of IL-1β than those with the C/C genotype. The AluYb8MUTYH genotype was strongly associated with increased IL-1β levels among controls and increased IL-1β and IL-6 levels among hemodialysis patients. Additionally, the synergetic effect of these variations of the BER genes on the levels of IL-1β and IL-6 was investigated. The combinations of the AluYb8MUTYH genotype with the hOGG1 c.977 C>G or MUTYH c.972 G>C genotypes were associated with the IL-1β and IL-6 levels in hemodialysis patients. This is the first report showing an association between BER genetic polymorphisms and the inflammatory state during hemodialysis; this association might be mediated by impaired anti-oxidant defense mechanisms.

    • "Furthermore , oxidative DNA damage, as measured by 8-oxoG, was positively associated with renal fibrosis , suggesting that MUTYH mediates tubulointerstitial damage [101] . Other studies have indicated that suppression of MUTYH may actually be protective of renal disease [102, 103] . Importantly , polymorphisms found in these DNA repair pathway genes have also been shown to increase the risk of ESRD progression in a cohort of mixedcause patients undergoing hemodialysis [102]. "
    [Show abstract] [Hide abstract] ABSTRACT: Diabetic kidney disease is one of the major microvascular complications of both type 1 and type 2 diabetes mellitus. Approximately 30% of patients with diabetes experience renal complications. Current clinical therapies can only mitigate the symptoms and delay the progression to end-stage renal disease, but not prevent or reverse it. Oxidative stress is an important player in the pathogenesis of diabetic nephropathy. The activity of reactive oxygen and nitrogen species (ROS/NS), which are by-products of the diabetic milieu, has been found to correlate with pathological changes observed in the diabetic kidney. However, many clinical studies have failed to establish that antioxidant therapy is renoprotective. The discovery that increased ROS/NS activity is linked to mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, cellular senescence, and cell death calls for a refined approach to antioxidant therapy. It is becoming clear that mitochondria play a key role in the generation of ROS/NS and their consequences on the cellular pathways involved in apoptotic cell death in the diabetic kidney. Oxidative stress has also been associated with necrosis via induction of mitochondrial permeability transition. This review highlights the importance of mitochondria in regulating redox balance, modulating cellular responses to oxidative stress, and influencing cell death pathways in diabetic kidney disease. ROS/NS-mediated cellular dysfunction corresponds with progressive disease in the diabetic kidney, and consequently represents an important clinical target. Based on this consideration, this review also examines current therapeutic interventions to prevent ROS/NS-derived injury in the diabetic kidney. These interventions, mainly aimed at reducing or preventing mitochondrial-generated oxidative stress, improving mitochondrialantioxidant defense, and maintaining mitochondrial integrity, may deliver alternative approaches to halt or prevent diabetic kidney disease. © 2015, Society for Biomedical Diabetes Research. All rights reserved.
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    • "Sun et al. have shown that a variant of the MUTYH gene (AluYb8MUTYH) is associated with increased DNA oxidative lesions and also increased IL-1 levels in plasma from healthy subjects [51]. Later, the same group showed the association of polymorphisms in OGG1 and MUTYH and increased levels of IL-1b and IL-6 in hemodialysis patients [52] ; however, the mechanisms involved remain un- known. Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the BER pathway and is the major AP-endonuclease in mammals. "
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