Renin-angiotensin and endothelial nitric oxide synthase gene polymorphisms are not associated with the risk of incident type 2 diabetes mellitus : a prospective cohort study

OBJECTIVE: The renin-angiotensin system and endothelial function have both been implicated in the pathogenesis of type 2 diabetes. The aim of this study was to assess the relationship between a set of well-characterized genetic variants of the renin-angiotensin system and the endothelial nitric oxide synthase (NOS3) gene and the incidence of type 2 diabetes. DESIGN: Prospective cohort study. SETTING: Women's Health Study, United States. SUBJECTS: A total of 24,309 Caucasian women free of diabetes at baseline. MAIN OUTCOME MEASURES: Six previously characterized single nucleotide polymorphisms (NOS3 rs1800779, NOS3 rs3918226, NOS3 rs1799983, ACE rs1799752, AGT rs699 and AGTR rs5186) were genotyped. Cox proportional-hazards models were constructed to compare the incidence of type 2 diabetes according to the different genotypes. RESULTS: During a median follow-up of 10.2 years (interquartile range 9.6-10.6 years), 999 women developed type 2 diabetes. The age-adjusted incidence rates across the six genotypes were very similar, and ranged from 3.7 to 4.8 cases/1000 person-years of follow-up. The multivariable adjusted hazard ratios (95% confidence intervals) for rs1800779, rs3918226, rs1799983, rs1799752, rs699, and rs5186 were 1.01 (0.92-1.10), 1.09 (0.93-1.27), 0.95 (0.86-1.05), 1.04 (0.95-1.14), 1.08 (0.98-1.18), 1.01 (0.91-1.11), confirming the lack of association between the genotypes and incident type 2 diabetes. Stratification by body mass index revealed essentially unchanged results. Finally, there was no association between NOS3-haplotypes and incident type 2 diabetes. CONCLUSION: We did not find an association between six well-characterized genetic polymorphisms of the renin-angiotensin system or the NOS3 gene and the occurrence of type 2 diabetes.