JCEM：湘雅医院刘昭前发现Ser165Pro和Ser257Pro多态性与T2DM相关

为了探讨在中国人群，两种新型β3–肾上腺素能受体（ADRB3）基因多态性（Ser165Pro和Ser257Pro）与2型糖尿病（T2DM）的关系，来自中 南大学湘雅医学院的刘昭前教授及其团队进行了一项研究（Two Novel Functional Single Nucleotide Polymorphisms of ADRB3Are Associated With Type 2 Diabetes in the Chinese Population ），该研究发现Ser165Pro和Ser257Pro多态性影响ADRB3功能，并与T2DM的易感性和发展显著相关。该研究结果在线发表在2013年5月2日的美国《临床内分泌代谢杂志》（The journal of clinical endocrinology & metabolism）上，该杂志影响因子为5.967。
该研究中，共入选650例T2DM患者和1337例健康受试者进行相关性研究。通过定点突变重新创建两个候选基因多态性，并在稳定转染人胚肾293和中国仓鼠卵巢–K1细胞过程中探讨他们对ADRB3表达和功能的影响。使用实时PCR、免疫印迹、共聚焦显微镜和cAMP分析分别确定mRNA、蛋白质表达、运输和ADRB3功能
该研究结果表明，2种基因多态性都与T2DM显著相关（Ser165Pro OR=2.060,95%CI=1.303–3.258；Ser257Pro OR=7.588,95%CI=1.639–35.138。伴有Ser165Pro C等位基因的T2DM患者比TT基因型的患者具有较高的糖化血红蛋白A1C、空腹血糖和餐后血糖值。该研究同样发现，伴有Ser257Pro C等位基因的T2DM患者比TT基因型携带者有更低的空腹血清胰岛素、餐后血清胰岛素和稳态模型评估的胰岛素抵抗水平。进一步的体外研究表明稳定表达ADRB3基因Ser165Pro和Ser257Pro突变体的细胞系表现出cAMP累积活性受损。然而，两种基因多态性对ADRB3表达和运输都没有影响。
该研究发现，Ser165Pro和Ser257Pro多态性影响ADRB3功能，并与T2DM的易感性和发展显著相关。

Two Novel Functional Single Nucleotide Polymorphisms of ADRB3 Are Associated With Type 2 Diabetes in the Chinese Population.
Abstract
Aims:The purpose of this study was to investigate the association of two novel β3-adrenergic receptor (ADRB3) gene polymorphisms (Ser165Pro and Ser257Pro) with type 2 diabetes (T2DM) in the Chinese population. Methods:A total of 650 patients with T2DM and 1337 health volunteers were enrolled to conduct the association study. Two candidate polymorphisms were recreated by site-directed mutagenesis and tested for their effect on ADRB3 expression and function in stable transfected human embryonic kidney 293 and Chinese hamster ovary-K1 cells. Real-time PCR, Western blot, confocal microscopy, and cAMP assay were used to determine mRNA, protein expression, trafficking, and ADRB3 function, respectively. Results:We found that both polymorphisms were significantly associated with T2DM (odds ratio = 2.060 and 95% confidence interval = 1.303-3.258 for Ser165Pro and odds ratio = 7.588, 95% confidence interval = 1.639-35.138 for Ser257Pro). Patients with T2DM with the Ser165Pro C allele had higher hemoglobin A1c, fasting plasma glucose and postprandial plasma glucose values than those in TT genotypes. We also found that patients with T2DM with the Ser257Pro C allele had lower fasting serum insulin, postprandial serum insulin, and homeostasis model assessment for insulin resistance levels than TT genotype carriers. Further in vitro study indicated that cell lines stably expressing Ser165Pro and Ser257Pro mutants of the ADRB3 gene showed impaired cAMP accumulation activity. However, both polymorphisms had no effect on ADRB3 expression and trafficking. Conclusions:Ser165Pro and Ser257Pro polymorphisms affected ADRB3 function and were significantly associated with susceptibility to and development of T2DM.