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.


METHODS
Prospective cohort study.


METHODS
Women's Health Study, United States.


METHODS
A total of 24,309 Caucasian women free of diabetes at baseline.


METHODS
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.


CONCLUSIONS
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.
Conen
D
D
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. conend@uhbs.ch
Glynn
R J
RJ
Buring
J E
JE
Ridker
P M
PM
Zee
R Y
RY
D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004812:Epidemiologic Methods; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D012084:Renin-Angiotensin System / Q000235:genetics*; D014481:United States
C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A