Risk of chronic kidney disease in type 2 diabetes determined by polymorphisms in NOS3, APOB, KCNJ11, TCF7L2 genes as compound effect of risk genotypes combination

Abstract

Genetic susceptibility plays an important role in the risk of developing chronic complications in patients with type 2 diabetes mellitus (T2DM). Aims: In this study, we evaluated the possible association of the polymorphic variants that encode key renal damage mediators (endothelial dysfunction, lipid metabolism and insulin secretion/sensitivity) with the risk of chronic kidney disease (CKD) in patients with T2DM. Materials and Methods: We enrolled 435 patients with T2DM using case-control study design. In 253 patients, we used non-overlapping criteria to form groups with/without CKD (defined as GFR<60 ml/min/1.73 m2) according to the duration of T2DM (≤5 years/≥10 years) (n=75 and 178, respectively) and analysed the following 4 polymorphic markers: I/D in ACE, ecNOS4a/4b in NOS3, I/D in APOB and e2/e3/e4 in APOE genes. We then divided 182 patients in groups with/without CKD (n=38 and 144, respectively) regardless of the duration of diabetes and studied pro12ala in PPARG2, rs5219 in KCNJ11, rs12255372 in TCF7L2 and rs13266634 in SLC30A8 genes. Statistical analysis was performed using the X2 test, and data were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Values of p <0.05 indicated statistical significance. Results: Four genes were found to have a significant association with CKD occurrence. For the eNOS3 the allele 4a and 4a/4a genotype was associated with a twofold CKD risk (OR=2.2/9.88) and the allele 4b and 4b/4b polymorphism were protective regarding CKD development (OR=0.44/0.45). For APOB I/D, the genotype DD was associated with lower risk of CKD [OR for DD=0.2 (95% CI: 0.05-0.88)]. In the second group, genotype TT of TCF7L2 predisposed to CKD (OR=3.03, 95% CI: 1.07-8.58). For KCNJ11 group genotype AA predisposed to CKD (OR=2.25, 95% CI: 1.02-4.97) compared to the allele G (OR=0,57, 95% CI: 0.34-0.96). Conclusions: In conclusion, our findings indicate a significant role of functional genetic variants associated with genes of endothelial factors (NOS3), lipid metabolism (APOB), and insulin secretion factors (KCNJ11, TCF7L2) in modulating the risk of CKD and their significant involvement in the mechanism of kidney damage in patients with T2DM.