Endothelial nitric oxide synthase gene polymorphisms and renal responsiveness to RAS inhibition therapy in type 2 diabetic Asian Indians.

Objective: To investigate the association of functional single nucleotide polymorphisms (SNPs) of the endothelial nitric oxide synthase gene (eNOS) gene (T-786C, G894T) and one variable number tandem repeat polymorphism (aa 27VNTR bb) with reno-protective response to angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) therapy in North Indian type 2 diabetic mellitus (T2DM) subjects with cases having diabetic nephropathy (DN) and controls without DN.

Methods: We genotyped three polymorphisms of eNOS (two SNPs: T-786C, G894T and one 27 VNTR) in T2DM patients with overt nephropathy (cases: n=320) and T2DM patients without overt nephropathy (controls: n=490), using validated PCR-RFLP assays. These 810 North Indian T2DM patients treated with ACEI or ARB after diagnosis were followed up for 3 years. Percent changes in eGFR, urinary albumin excretion (UAE), serum creatinine at the end of 3 years of treatment were taken as end points of renoprotective response.

Results: We observed that in normoalbuminuric patients, eNOS -786 CC genotype and haplotypes C-b-G and C-b-T were associated with lesser renoprotective response to ACEI. While, in macroalbuminurics, eNOS -786 CC genotype, haplotypes C-b-G and C-b-T and 27VNTR aa were associated with better renoprotective response to ACEI/ARB.

Conclusions: Our results showed that eNOS T-786C CC genotype and 27VNTR individually and in interaction with other eNOS SNPs modulate renoprotective efficacy of ACEI and ARB in T2DM patients, depending on the status of proteinuria.