Bressler Jan, Pankow James S, Coresh Josef, Boerwinkle Eric
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
PLoS One. 2013 Nov 20;8(11):e79466. doi: 10.1371/journal.pone.0079466. eCollection 2013.
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/m(2) 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/m(2) 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.
内皮型一氧化氮合酶3（NOS3）催化内皮细胞中由L-精氨酸生成一氧化氮。肥胖是糖尿病的一个可改变的风险因素，据报道，与体重在正常范围内的对照组相比，肥胖个体的一氧化氮可用性降低。由于预测NOS3 G894T变异的纯合携带者酶活性降低，因此评估了NOS3基因型与2型糖尿病之间的关联以及体重指数（BMI）可能产生的效应修饰作用。在美国四个社区开展的基于社区的前瞻性双种族动脉粥样硬化风险（ARIC）研究中，对14374名45 - 66岁参与者的糖尿病患病率和BMI在基线时进行了测定。BMI≥30 kg/m²的个体被视为肥胖。那些不符合病例定义的受试者作为728名非裔美国糖尿病患者和980名白人糖尿病患者的对照组。使用对年龄、性别和研究中心进行校正的多变量逻辑回归模型来检验主要遗传效应以及与肥胖的相互作用。尽管在非裔美国人或白人中，NOS3 G894T变异均未独立与糖尿病相关，但BMI与NOS3多态性之间存在显著相互作用，表明肥胖是TT基因型白人个体糖尿病风险的效应修饰因素（相互作用的比值比（OR） = 1.65，p = 0.04）。在分层分析中，与常见的GG基因型相比，肥胖白人参与者而非BMI < 30 kg/m²的参与者中，NOS3 T等位基因纯合与糖尿病风险升高相关（OR = 1.47，p = 0.02）。这些结果表明，肥胖与NOS3基因型之间的相互作用可能是ARIC队列中白人糖尿病病例状态的一个决定因素。需要在其他人群中进行重复研究以证实这些观察结果。
