Polymorphisms in glucose homeostasis genes are associated with cardiovascular and renal parameters in patients with diabetic nephropathy

Abstract

Background: Diabetic nephropathy (DN) has become the major cause of end-stage kidney disease and is associated to an extremely high cardiovascular (CV) risk.

Methods: We screened 318 DN patients for 23 SNPs in four glucose transporters (SLC2A1, SLC2A2, SLC5A1 and SLC5A2) and in KCNJ11 and ABCC8, which participate in insulin secretion. Regression models were utilised to identify associations with renal parameters, atherosclerosis measurements and CV events. In addition, 506 individuals with normal renal function were also genotyped as a control group.

Results: In the patient's cohort, common carotid intima media thickness values were higher in carriers of ABCC8 rs3758953 and rs2188966 vs. non-carriers [0.78(0.25) vs. 0.72(0.22) mm, p < 0.05 and 0.79(0.26) vs. 0.72(0.22) mm, p < 0.05], respectively. Furthermore, ABCC8 rs1799859 was linked to presence of plaque in these patients [1.89(1.03-3.46), p < 0.05]. Two variants, SLC2A2 rs8192675 and SLC5A2 rs9924771, were associated with better [OR = 0.49 (0.30-0.81), p < 0.01] and worse [OR = 1.92 (1.15-3.21), p < 0.05] CV event-free survival, respectively. With regard to renal variables, rs841848 and rs710218 in SLC2A1, as well as rs3813008 in SLC5A2, significantly altered estimated glomerular filtration rate values [carriers vs. non-carriers: 30.41(22.57) vs. 28.25(20.10), p < 0.05; 28.95(21.11) vs. 29.52(21.66), p < 0.05 and 32.03(18.06) vs. 28.14(23.06) ml/min/1.73 m², p < 0.05]. In addition, ABCC8 rs3758947 was associated with higher albumin-to-creatinine ratios [193.5(1139.91) vs. 160(652.90) mg/g, p < 0.05]. The epistasis analysis of SNP-pairs interactions showed that ABCC8 rs3758947 interacted with several SNPs in SLC2A2 to significantly affect CV events (p < 0.01). No SNPs were associated with DN risk.

Conclusions: Polymorphisms in genes determining glucose homeostasis may play a relevant role in renal parameters and CV-related outcomes of DN patients.

Keywords: Chronic kidney disease; diabetic kidney disease; diabetic nephropathy; glucose homeostasis; type 2 diabetes mellitus.

Figure 1.

Estimated glomerular filtration rate (eGFR) values according to the presence of rs710218 (A), rs841848 (B) and rs3813008 (C) variants, and albumin-to-creatinine ratios (ACR) distributed by rs3758947 genotypes (D) in patients with diabetic nephropathy. Manhattan plots show the p-value for the association of all the SNPs studied regarding eGFR (E) and ACR (F). *p < 0.05.

Figure 2.

Distribution of common carotid intima media thickness (CCIMT) values according to different genotypes of ABCC8 in patients with diabetic nephropathy. The Manhattan plot shows the p-value for the association of all the SNPs studied. *p < 0.05.

Figure 3.

Kaplan–Meier curves depicting cardiovascular event-free survival in patients with diabetic nephropathy carrying the SLC2A2 rs8192675 (A) or SLC5A2 rs9924771 (B) polymorphisms.

Figure 4.

Effect of interactions between SNPs in glucose homeostasis genes on several clinical phenotypes in CKD patients. Significant hits discussed in the text are highlighted in red. The diagonal line contains the P values from likelihood ratio test for the crude effect of each SNP, which are sorted by their genomic position. The upper triangle in the matrix contains the P values for the interaction (epistasis) log-likelihood ratio test. Finally, the lower triangle contains the P values from likelihood ratio test comparing the two-SNP additive likelihood to the best of the single-SNP models. eGFR: estimated glomerular filtration rate (ml/min/1.73 m²); ACR: albumin-to-creatinine ratio (mg/g); CV: cardiovascular; CCIMT: common carotid intima media thickness.