The association between diabetic nephropathy and polymorphisms in PPARγ Pro 12Ala and CCR5δ 32 genes in type 2 diabetes

Abstract

Introduction and Aims: Diabetic nephropathy is a debilitating complication of type 2 diabetes and a leading cause for end stage renal disease requiring renal replacement therapy. Currently identified risk factors do not fully explain the susceptibility of some patients to develop diabetic nephropathy. Peroxisome Proliferator Activated Receptor gamma (PPAR (gamma)) Pro12Ala gene polymorphisms modulate insulin sensitivity and oxidative stress in diabetics and conflicting data exist on its association with kidney disease in diabetes. Several polymorphisms of another immune modulator set of genes, the C-C Chemokine Receptor5 (CCR 5) genes were associated with diabetic nephropathy. However, CCR5 (delta) 32 gene polymorphism, was not studied in diabetic nephropathy patients.We aim to study the association between polymorphisms of both, the PPAR (gamma) Pro12Ala and CCR5 (delta) 32 genes with the presence of diabetic nephropathy in Egyptian type 2 diabetic patients. Methods:We included 51 patients diagnosed with type 2 diabetes of at least 5 years duration. They were all normotensive patients with no other clinically identifiable risk factor for kidney disease from the out-patient clinic. Genotype detection for PPAR (gamma) Pro 12Ala and CCR5 (delta)32 gene polymorphisms were carried out by PCR. Clinical data, HbA1c, lipid profile, fasting and postprandial blood sugar were recorded. serum creatinine and urinary albumin/creatinine ratio were measured to stratify the participants according to presence or absence of diabetic nephropathy. Results: Age, gender, body mass index, HbA1c and duration of diabetes were not significantly different among those with and those without diabetic nephropathy. Diabetic nephropathy patients had higher urinary albumin/creatinine ratio and lower eGFR (p<0.0001). Homozygotes for the PPAR (gamma) Pro12Ala Pro-Pro allele constituted 82% of our total study population, and 86.4% of those with diabetic nephropathy; the remaining were Pro-Ala heterozygotes.. The odds ratio for diabetic nephropathy in Pro-Pro homozygotes was 3.5, p=0.075, 95% CI 0.8-15 compared to heterozygotes. The Pro allele was present in 75% of those with nephropathy and 50% of those with no nephropathy. The Pro allele was significantly associated with diabetic nephropathy compared to the Ala allele: odds ratio = 3.5, p= 0.012, 95% CI 1.3-15. Regarding the CCR5 (delta)32 insertion/deletion genotype, 24 patients were homozygous for insertion polymorphism, 2 were homozygous for the deletion polymorphism and the remaining 25 were insertion/deletion heterozygotes. There was no significant difference between nephropathic and non-nephropathic patients regarding the CCR5 (delta)32 genotype (p=0.3) nor the frequency of allele distribution, p= 0.6. Conclusions: Polymorphisms of PPAR(gamma)- Pro12Ala were associated with diabetic nephropathy whereas polymorphisms of CCR5(delta) 32 gene showed no association.