Review of genetic association in the SOD2 gene with chronic kidney disease: case-control studies and meta-analysis confirm association with diabetic nephropathy

The SOD2 gene encodes a mitochondrial protein that is involved with response to oxidative stress and cellular proliferation. The diabetic milieu, in particular hyperglycemia, results in the overproduction of superoxide and formation of secondary reactive oxygen species contributing to the accumulation of DNA, protein and cellular damage. Functional genetic variants within the SOD2 gene are postulated to influence renal injury. We sought to resolve the inconsistent conclusions of several studies examining the SOD2 gene for association with chronic kidney disease, in particular diabetic nephropathy. We genotyped a total of 3913 individuals with diabetic nephropathy, glomerulonephritis and/or end-stage renal disease, reviewed published literature, and conducted a subsequent meta-analysis. Using x2 test, our independent case-control study for diabetic nephropathy revealed evidence for association of rs4880 (P=0.01). However, this was ameliorated by adjusting for age at diagnosis, duration, sex and recruitment centre in the logistical model. Genotype counts were obtained for all published studies having genotyped this SNP and a meta-analysis was performed on a total of 3949 individuals with type 1 diabetes mellitus (cases n=2,184; controls, n=1,765). No significant heterogeneity was observed (P=0.5) and association with diabetic nephropathy was supported by P=0.005 (odds ratio 0.87, 95% confidence interval: 0.79-0.96). There is biological evidence that this amino-acid changing SNP, rs4880, directly influences enzymatic activity of the SOD2 gene product. We conclude that the functional, clinically associated rs4880 is important in the pathogenesis of diabetic nephropathy.