Associations Between Genetic Polymorphisms in the VEGFA, ACE, and SOD2 Genes and Susceptibility to Diabetic Nephropathy in the Han Chinese

Objective: To investigate the association between polymorphisms in the rs2010963 and rs69947 loci of the vascular endothelial growth factor A (VEGFA) gene; the rs4646994 locus of the angiotensin I converting enzyme (ACE) gene; and the rs4880 locus of the superoxide dismutase 2 (SOD2) gene with genetic susceptibility to type 2 diabetic nephropathy (T2DN) in the Chinese Han population. Methods: A total of 650 Chinese Han patients with T2DN and 580 non-nephropathy patients with type 2 diabetes were enrolled in this study. Sanger sequencing was used to detect the genotypes of the rs2010963 and rs69947 loci within VEGFA, the rs4646994 locus of for the ACE gene, and the rs4880 locus of the SOD2 gene in all subjects. Enzyme-linked immunosorbent assays were used to detect VEGFA, ACE, and SOD2 levels in serum. Results: The risk of T2DN was significantly increased (odds ratio [OR] = 1.15, confidence interval [95% CI]: 1.03-1.30) in patients with the GC/CC genotypes compared to those with the GG genotype at the rs2010963 locus of the VEGFA gene under the dominant model of inheritance. Similarly, the risk of T2DN was significantly increased (OR = 1.17, 95% CI: 1.05-1.31) in patients with the CA/AA genotypes compared to those with the CC genotype at the rs69947 locus of the VEGFA gene under the dominant model of inheritance. In addition, the risk of T2DN was increased (OR = 1.57, 95% CI: 1.37-1.74) in patients with the AA genotype compared to the CC/CA genotypes under the recessive model of inheritance. The risk of T2DN was also significantly increased (OR = 1.54, 95% CI: 1.24-1.97) in patients with the ID/DD genotypes compared to those with the II genotype at the rs4646994 locus of the ACE gene under the dominant model; and (OR = 1.41, 95% CI: 1.26-1.57) for DD genotype compared to the II/ID genotypes under the recessive model. We also found the risk of T2DN was significantly increased (OR = 1.25, 95% CI: 1.11-1.39) under the dominant model in patients with the TC/CC genotypes compared to the TT genotype, and for the CC genotype (compared to the TT/TC genotype) (OR = 1.45, 95% CI: 1.18-1.66) under the recessive model at the rs4880 locus of the SOD2 gene rs4880. The haplotypes GAC (OR = 1.17, 95% CI: 1.04-1.29), CAT (OR = 1.12, 95% CI: 1.03-1.60), and CAC (OR = 1.13, 95% CI: 1.01-1.24) constructed from VEGFA gene rs2010963 and rs69947 loci, and the SOD2 gene rs4880 locus were associated with a higher risk for T2DN. Finally, we found that VEGFA protein levels from subjects with the rs2010963 GG genotype and the rs69947 CC genotype were higher in both case groups and the control group than in subjects with rs2010963 GA/AA genotypes and rs69947 CA/AA genotypes, respectively (p < 0.05). The ACE protein levels for variants at the rs4646994 locus showed that the case group and control group subjects with the DD genotype had the highest levels, followed by the ID genotype and the II genotype (p < 0.05). Conclusion: Genetic variation in the VEGFA gene at the rs2010963 and rs69947 loci, the ACE gene at the rs4646994 locus, and the SOD2 gene at the rs4880 locus may increase the risk of developing T2DN.