Wolford Johanna K, Colligan Peter B, Gruber Jonathan D, Bogardus Clifton
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 4212 North 16th Street, Phoenix, AZ 85016, USA.
Mol Genet Metab. 2003 Nov;80(3):338-43. doi: 10.1016/j.ymgme.2003.07.003.
Circulating levels of the cytokine interleukin 6 (IL-6) are elevated in obesity, correlate with body mass index (BMI), and predict the development of type 2 diabetes mellitus (T2DM). A promoter polymorphism in the IL6 gene is associated with obesity, altered levels of insulin sensitivity, and T2DM. IL-6 exerts its effects by binding to the IL-6 receptor (IL-6R) and levels of IL-6R have been correlated with BMI. It is possible that IL6R variants may also be related to obesity, but to our knowledge, no study has yet examined this relationship. The objective of this study was to examine the relationship between genetic variants in the IL6R gene and obesity in Pima Indians, a population prone to excess adiposity. We sequenced 6kb of the IL6R gene, corresponding to all exons, exon-intron boundaries, and 2kb of promoter in 30 Pima Indians. We identified six single nucleotide polymorphisms (SNPs) in the IL6R gene: a predicted Asp --> Ala substitution at position 358, a variant in the 3'-untranslated region, and 4 intronic SNPs. All SNPs were in strong linkage disequilibrium (D' >/= 0.90) and varied in minor allele frequency from 0.33 to 0.48. Association between IL6R genotype and BMI (kg/m(2)) was assessed in approximately 700 nondiabetic, full-heritage Pima Indians. For each SNP, individuals carrying the variant allele had a higher mean BMI compared to those with the wild-type allele (range: [37.3+/-7.2-38.2+/-7.0] vs. [35.5+/-7.3-36.0+/-7.5]; P=0.02-0.004). Our findings suggest that genetic variants in the IL6R gene may play a role in susceptibility to obesity. Assessment of these SNPs in other populations will be useful to determine the magnitude of obesity risk.
细胞因子白细胞介素6（IL-6）的循环水平在肥胖症中升高，与体重指数（BMI）相关，并可预测2型糖尿病（T2DM）的发生。IL6基因中的启动子多态性与肥胖症、胰岛素敏感性改变及T2DM有关。IL-6通过与IL-6受体（IL-6R）结合发挥作用，且IL-6R水平与BMI相关。IL6R变异体也可能与肥胖症有关，但据我们所知，尚无研究探讨这种关系。本研究的目的是在易患肥胖症的皮马印第安人群中，研究IL6R基因中的遗传变异与肥胖症之间的关系。我们对30名皮马印第安人的IL6R基因6kb区域进行了测序，该区域对应所有外显子、外显子-内含子边界及2kb启动子。我们在IL6R基因中鉴定出6个单核苷酸多态性（SNP）：预测的第358位天冬氨酸（Asp）到丙氨酸（Ala）的替换、3'-非翻译区的一个变异体以及4个内含子SNP。所有SNP均处于强连锁不平衡状态（D'≥0.90），次要等位基因频率在0.33至0.48之间。在约700名非糖尿病、纯种皮马印第安人中评估了IL6R基因型与BMI（kg/m²）之间的关联。对于每个SNP，携带变异等位基因的个体的平均BMI高于携带野生型等位基因的个体（范围：[37.3±7.2 - 38.2±7.0] 对 [35.5±7.3 - 36.0±7.5]；P = 0.02 - 0.004）。我们的研究结果表明，IL6R基因中的遗传变异可能在肥胖症易感性中起作用。在其他人群中评估这些SNP将有助于确定肥胖风险的大小。
