Association between A1166C Polymorphism of the Angiotensin II Type-1 Receptor Gene and Type-2 Diabetic Nephropathy in an Indonesian Malay Population.

BACKGROUND: diabetic nephropathy (DN) is the leading cause of blood dialysis worldwide and a major etiology of End-Stage Renal Disease cases in Indonesia. Previous studies showed a relevant link between A1166C polymorphism of Angiotensin II Type-1 Receptor (AT1R) gene and glomerular hyper-filtration as a part of pathogenesis of DN. The aim of this study was to elaborate the association between A1166C AT1R polymorphism and susceptibility of individual with type-2 diabetes to DN in Malay Indonesian population. METHODS: a case-control study of 120 consecutive patients with type-2 diabetes mellitus (40 patients in each groups for macro-albuminuria, micro-albuminuria, and normo-albuminuria) was conducted for A1166C AT1R gene polymorphism. The A1166C polymorphism of the AT1R gene was determined based on PCR/RFLP. RESULTS: the mutant C allele was found in 5%, 13.75%, and 12.5% in normo-, micro-, and macro-albuminuria patients respectively. The heterozygote AC genotype was found significantly higher in micro-albuminuria, compared to normo-albuminuria group. Heterozygote AC genotype (OR 3.2 [1.01-10.08], p=0.03) and C allele (OR 2.8[0.95-8.67], p=0.038) were significantly higher in DN, indicating A1166C AT1R gene polymorphism as a risk factor for DN in Malay Indonesian population with type-2 diabetes. CONCLUSION: there was positive association between A1166C AT1R polymorphism and susceptibility of type-2 diabetics to DN in Malay Indonesian Population. It also indicated that the A1166C AT1R polymorphism could play a role in early pathogenesis of DN.

Why does diabetes mellitus increase the risk of cardiovascular disease?

The main etiology for mortality and a great percentage of morbidity in patients with diabetes mellitus is atherosclerosis. The pathogenesis of cardiovascular disease (CVD) in diabetes is multifactorial and can be affected by metabolic and other factors. A hypothesis for the initial lesion of atherosclerosis is endothelial dysfunction, defined pragmatically as changes in the concentration of the chemical messengers produced by the endothelial cell and/or by blunting of the nitric oxide-dependent vasodilatory response to acetylcholine or hyperemia. Endothelial dysfunction has been documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes. The way endothelial function altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Factors associated with endothelial dysfunction in diabetes include activation of protein kinase C, overexpression of growth factors and/or cytokines, and oxidative stress. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.