Diabetes mellitus, superoxide dismutase and peroxisome proliferator activated receptor gamma polymorphisms modify the outcome of end‐stage renal disease patients of Han Chinese origin

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Diabetes mellitus (DM) is characterized by a state of increased oxidative stress, resulting from the hyperglycaemia‐induced formation of advanced glycation endproduct (AGE) and other glycated molecules, as well as an impairment in antioxidative capacity.1 Increased oxidative stress, elevated inflammation severity, and metabolic perturbation in patients with DM potentially lead to endothelial injury, coagulation abnormality, and the development of multiple diabetic complications, including nephropathy and microvascular damages.1 Monitoring redox status using reactive oxygen species (ROS) markers (malondialdehyde, advanced oxidation protein products, or urine isoprostane) or antioxidants levels (erythrocyte glutathione levels or superoxide dismutase [SOD] activities) has also been found to correlate with disease activity and therapeutic responses among patients with DM.3 Patients with chronic kidney disease and end‐stage renal disease (ESRD) also exhibit a pro‐inflammatory status and have higher levels of oxidative stress, leading to an increased risk of developing cardiovascular diseases.5
Judging from the importance of oxidative stress and antioxidants in the pathogenesis of DM and ESRD, it is likely that polymorphisms of antioxidant genes might affect the risk of developing DM, progression to ESRD, and the outcomes of diabetic patients with or without ESRD. Several reports have suggested that single nucleotide polymorphisms (SNPs) of SOD2 and glutathione peroxidase 1 (GPX1) were associated with altered risk of diabetic nephropathy, neuropathy, and coronary artery disease among patients with DM.6 Certain SNP of the GPX1 gene is also found to increase the risk of renal events among patients with type 1 DM, and correlates with higher plasma ROS markers.8 Previously, we also discovered that TT genotype of exon 2 of the SOD2 gene (rs4880) conferred a significantly lower risk of presenting ESRD among patients without DM (P = 0.014).9 On the other hand, very few studies address the effect of antioxidant SNPs on the survival of ESRD patients. Anecdotal reports suggest that SOD1 allelic variations is associated with higher risk of mortality, especially of cardiovascular causes, among patients with DM, and increased oxidative stress has been attributed as the main culprit.10 Subgroup analysis from a cohort of patients with myocardial infarction and chronic kidney disease (CKD) revealed that a SNP of paraoxonase 1, a lipoprotein antioxidant, also increased their mortality.11 However, none of the existing studies focus on the effect of SNPs on the mortality of ESRD patients of Han Chinese population; furthermore, a study addressing the interaction between DM, antioxidant SNPs, and SNPs of metabolism‐related genes such as peroxisome proliferator activated receptor‐γ (PPAR‐γ) is still unavailable. In addition, identifying SNPs with outcome influence in ESRD patients can help uncover an important pathophysiological mechanism with treatment potential. Consequently, using a prospectively collected cohort, we investigated the effect of different antioxidant SNPs, PPAR‐γ SNPs, DM, and their interactions on the survival of ESRD patients of Han Chinese origin.
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