Abstract
Endothelial nitric oxide synthase 3 (NOS3) catalyzes the production of nitric oxide from L-arginine in endothelial cells. Obesity is a modifiable risk factor for diabetes, and obese individuals have been reported to have reduced nitric oxide availability compared to controls whose weight is in the normal range. Since homozygous carriers of the NOS3 G894T variant are predicted to have decreased enzyme activity, the association between NOS3 genotype and type 2 diabetes, and possible effect modification by body mass index (BMI) were evaluated. The prevalence of diabetes and BMI was determined at baseline in 14,374 participants 45–66 years of age from the prospective biracial population-based Atherosclerosis Risk in Communities (ARIC) Study of the development of atherosclerosis in four communities in the United States. Individuals with a BMI ≥30 kg/m2 were considered obese. Those subjects not meeting the case definition were the comparison groups for the 728 African American and 980 white participants with diabetes. Multivariable logistic regression models adjusted for age, sex, and field center were used to test for main genetic effects and interaction with obesity. Although the NOS3 G894T variant was not independently associated with diabetes in either African Americans or whites, significant interaction between BMI and the NOS3 polymorphism indicated that obesity was an effect modifier of diabetes risk for white individuals with the TT genotype (odds ratio (OR) for interaction = 1.65, p = 0.04). In stratified analyses, homozygosity for the NOS3 T allele in obese white participants but not in those whose BMI <30 kg/m2 was associated with an elevated risk of diabetes (OR = 1.47, p = 0.02) when compared to the common GG genotype. These results suggest that interaction between obesity and NOS3 genotype may be a determinant of diabetes case status in whites in the ARIC cohort. Replication in other populations will be required to confirm these observations.
Highlights
Diabetes is an important and treatable risk factor for cardiovascular disease. [1] Obesity is an independent risk factor for diabetes and body mass index (BMI) has been commonly used as an index of adiposity. [2] Nitric oxide (NO) is produced by endothelial cells and has been implicated in vascular relaxation in response to multiple agents including acetylcholine, an activity originally attributed to endothelium-derived relaxing factor (EDRF). [3] NO has been shown to have a role in the regulation of blood pressure and vascular tone [4]
The allele and genotype frequencies for the nitric oxide synthase 3 (NOS3) polymorphism were in accordance with Hardy-Weinberg equilibrium expectations for both African American (p = 0.62) and white (p = 0.95) individuals in the study, and are consistent with those previously reported for the Yoruba in Ibadan, Nigeria and CEPH (Utah residents with ancestry from northern and western Europe) populations included in the International HapMap Project, [39] and in a study of candidate genes associated with childhood obesity
In contrast to the results described above, the effect of NOS3 G894T genotype on diabetes case status did not appear to vary with level of BMI in African American participants (Table 4) there are only a small number of individuals with the TT genotype reflecting the low minor allele frequency (Table 2)
Summary
Diabetes is an important and treatable risk factor for cardiovascular disease. [1] Obesity is an independent risk factor for diabetes and body mass index (BMI) has been commonly used as an index of adiposity. [2] Nitric oxide (NO) is produced by endothelial cells and has been implicated in vascular relaxation in response to multiple agents including acetylcholine, an activity originally attributed to endothelium-derived relaxing factor (EDRF). [3] NO has been shown to have a role in the regulation of blood pressure and vascular tone [4]. An association between the NOS3 G894T (Glu298Asp) single nucleotide polymorphism (SNP) and myocardial infarction, coronary artery disease, stroke, and hypertension has been previously reported none of these studies included African Americans [6,7,8,9,10,11,12,13,14,15]. There was no increased risk for diabetes found in Mexican-American participants in the San Antonio Family Diabetes/Gallbladder Study or for type 2 diabetes patients when compared to controls from Japan, Taiwan, or Finland [20,21,22,23]. The NOS3 G894T genetic variant was not associated with albuminuria in European American families, with insulin resistance in subjects with and without diabetes in Japan, with renal disease or diabetic retinopathy in Brazilians with diabetes, or with diabetic retinopathy in a systematic meta-analysis that combined the results of four genetic association studies [24,25,26,27,28]
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