Aim: Renin, a component of the Renin-Angiotensin-Aldosterone System (RAAS), is produced in the juxtaglomerular cells of the kidney. It is an important factor for the regulation of blood pressure and electrolyte balance and encoded by the REN gene. Recent studies suggest that the RAAS is a regulator of kidney functions. Individuals with REN variants have been associated with high blood pressure. We substantiated the hypothesis that genetic variants of REN gene have significant association with prevalence of nephropathy and in the development of nephropathy in type 2 diabetes mellitus (T2DM). Methods: We enrolled to the study 718 consecutive subjects who were registered patients in two individual hospitals in Kolkata city, India. They consisted of 246 (34.26%) T2DM patients without nephropathy cases, 168 (23.40%) type 2 diabetes with nephropathy cases (T2DNH) and 304 (42.34%) healthy controls. Genotypes were assayed with genomic DNA for two known variants of the REN gene, i.e., rs16853055 and rs41317140 using sequencing methods. Results: Association between the REN gene variants and prevalence of T2DM and T2DNH was tested. A significant association of T2DNH and variant rs41317140 was obtained and it was evident that the rs41317140 (C>T) shows a significant difference between T2DM and T2DNH (x 2 = 4.92; P = 0.03; OR = 0.6162; 95% CI: 0.4006-0.948). The results from the multiple model test that additive model predicted the association at genotype level and shows a significant difference between T2DM and T2DNH (OR = 0.6067; P = 0.03). There was no significant association between T2DNH or T2DM and variant rs16853055. Conclusion: Thus, it is concluded that a genetic variant of the REN gene should have a significant impact on the onset of type 2 diabetic nephropathy.