Correlation between polymorphisms of SIRT2 gene and renal injury in patients with type 2 diabetes mellitus.

Objectives: Genetic factors play an important role in the pathogenesis of diabetic kidney disease (DKD). Studies have shown that SIRT2 gene polymorphism is associated with the pathogenesis of type 2 diabetes mellitus (T2DM), but its role in DKD remains unclear. This study aims to analyze the distribution of alleles and genotypes of SIRT2 gene in patients with T2DM, and investigate the association between SIRT2 genetic polymorphism and DKD susceptibility in T2DM patients, which may provide new ideas for the pathogenesis of DKD.

Methods: A toal of 205 T2DM patients who receiving treatment in the Third Xiangya Hospital of Central South University were divided into a DKD group (n=100) and a DM group (n=105) according to the presence of kidney injury, and 100 healthy volunteers were selected as NC group. Clinical data of the subjects were collected and estimated glomerular filtration rate (eGFR) were calculated. Genomic DNA was extracted and the genotypes of single nucleotide polymorphism (SNP) loci (rs11879029, rs11879010, and rs2241703) were determined using Sanger chain termination method. The genotype/allele frequencies among the 3 groups were compared. Logistic regression was used to analyze the correlation between SNP locus genotype of SIRT2 gene and risk of DKD in T2DM patients. According to the genotypes of rs11879029/rs11879010, T2DM patients were divided into a GG1/GG2 group, a GA1/GA2 group, and an AA1/AA2 group, and the clinical data were compared. Linkage disequilibrium analysis and haplotype analysis were performed.

Results: The genotype distribution and allele frequencies of the rs11879029 and rs11879010 loci in the DKD group were significantly different in comparison with the NC and DM groups (all P<0.05). For rs2241703, there were no differences in genotype and allele frequencies (all P>0.05). After correcting by age, gender, systolic blood pressure, duration of diabetes, glycosylated hemoglobin, and serum albumin, rs11879029 and rs11879010 genotype were associated with DKD susceptibility in T2DM patients. Carriers of rs11879029 genotype AA were 6.27 times more likely to have DKD than carriers of genotype GG. And carriers of rs11879010 genotype AA were 4.72 times more likely to have DKD than carriers of genotype GG. The eGFR levels in the AA1/AA2 groups were significantly lower than those in the GG1/GG2 groups (both P<0.05). Analysis of linkage disequilibrium showed complete linkage disequilibrium existed between SIRT2 rs11879029 and rs11879010, and the 2 SNPs (rs11879029 and rs11879010) were in strong linkage disequilibrium with rs2241703. Monotype GGG reduced the risk of DKD in T2DM patients (OR=0.53, 95% CI 0.35 to 0.81, P=0.003), while haplotype AAG increased the risk of DKD in patients (OR=1.80, 95% CI 1.16 to 2.80, P=0.008).

Conclusions: The genetic polymorphisms rs11879029 and rs11879010 of SIRT2 gene are potential contributors to the susceptibility of DKD in patients with T2DM, and allele A significantly increases the risk of DKD compared with allele G. The AA genotype might be a genetic risk factor for DKD.