维生素D和维生素D受体基因多态性在2型糖尿病发病中的作用研究

The type 2 diabetes mellitus (T2DM) is caused by a combination of genetics and environment risk factors. Although some environmental factors and susceptible genes related to T2DM have been identified, the pathogenesis of T2DM remains unclear. Recent studies indicated that vitamin D (Vit D) deficiency and vitamin D receptor (VDR) gene polymorphism have been related with the pathogenesis of T2DM. Based on the previous studies, the epidemiological cross-sectional survery, case-control family and individual intervention experiments on Vit D will be performed in this project. Firstly, the relationship between the Vit D level and the relevant biochemical parameters in particpants with T2DM was researched by cross-sectional survey. Secondly, the relationship between the VDR gene polymorphism and T2DM will be investigated and analyzed by the case-control family design. In addition, the gene-gene interaction and gene-environment interaction will be analyzed by case-control family study, and then the combined effects were evaluated on genetic susceptibility and enrivonment factors in T2DM by multifactor dimensionality reduction (MDR) and classification and regression tree (CART) model. Thirdly, the role of Vit D in T2DM development process was systematically evaluated by individual intervention experiments. The findings of this study not only could help to explor the relationship between Vit D and VDR gene with T2DM, but also to elucidate the interaction between genetic susceptibility and environment factors for T2DM, and then could provide evidence for evaluating the high risk factors, and establishing individualized prevention and control strategy for T2DM.

2型糖尿病（T2DM）是遗传因素与环境因素共同作用的结果，虽已发现一些易感基因和环境因素与T2DM相关，但其病因和发病机制尚未完全阐明。近年来有研究显示，T2DM的发生可能与血清维生素D（Vit D）缺乏和维生素D受体（VDR）基因变异有关。因此，申请者拟在前期相关研究的基础上开展Vit D流行病学现况调查、病例对照遗传家系、个体干预实验等多阶段研究。采用现况调查阐述Vit D营养水平及相关生化指标与T2DM之间的关系；采用病例对照家系研究探讨VDR基因与T2DM的遗传关联，联合应用MDR和CART模型分析基因-环境的交互作用；通过口服Vit D个体干预试验系统评价Vit D在T2DM病程发展过程中的作用。研究结果不仅有助于全面认识Vit D及VDR基因多态性在T2DM发病中的作用，而且有助于为T2DM高发风险的估计、个体化预防及综合防治措施的制定和实施提供科学依据。

2型糖尿病是遗传因素与环境因素相互作用的一种慢性非传染性疾病，也是目前人类面临的重大公共卫生问题之一。虽已发现一些易感基因和环境因素与2型糖尿病相关，但其病因和发病机制尚未完全阐明。近年来有研究显示，维生素D可影响胰岛β细胞的功能，2型糖尿病的发生可能与体内维生素D缺乏和维生素D受体基因变异有关。本研究在前期相关研究的基础上，开展了下列两方面的研究工作，①采用现况调查阐述中国农村人群维生素D水平与2型糖尿病之间的关系；②采用2型糖尿病病例对照家系研究探讨维生素D受体基因与2型糖尿病的遗传关联，应用多因子降维模型分析基因-环境的交互作用。现况调查研究结果显示，中国农村人群普遍存在维生素D缺乏 (48.06%) 或不足 (14.94%)的现象，维生素D水平正常人群的仅占36.99%；与维生素D水平正常人群相比，缺乏和不足人群2型糖尿病的易感性显著增加，其比值比（OR）及95%可信区间（CI）分别为1.815(1.390, 2.371) 和1.589(1.157, 2.183)。家系研究结果显示，2型糖尿病具有明显的家族聚集性，其一级亲属的遗传度为(0.66±0.09)%。维生素D受体基因多态性与T2DM遗传易感性分析发现，在全人群中VDR基因rs2189480和rs2239179位点多态性与T2DM发病存在统计学关联 (P<0.05)，在对照家系人群中rs7975232、rs2189480和rs3847987位点多态性与T2DM发病存在统计学关联 (P<0.05)，但在病例家系人群中未观察到上述位点与T2DM发病存在统计学关联(P>0.05)。基因-环境交互作用分析发现rs2189480位点多态性、吸烟、较多果蔬摄入之间存在交互作用。总之，农村居民广泛存在机体维生素D水平不足或缺乏现象，维生素D缺乏或不足及维生素D受体基因遗传变异与T2DM发病相关，rs2189480位点多态性、较多果蔬摄入、吸烟对T2DM的发生存在交互作用。相关研究结果不仅为掌握现阶段中国农村人群维生素D分布现状提供了基线资料，而且为全面认识维生素D及维生素D受体基因多态性在2型糖尿病发病中的作用提供了科学依据。