KCNQ1基因多态性和DNA甲基化与妊娠期糖尿病发病风险的关联及交互作用研究

妊娠期糖尿病（GDM）是危害母儿近、远期健康的公共卫生问题。KCNQ1基因与GDM发生的病理生理学基础—胰岛素分泌异常和胰岛素抵抗密切相关。我们前期研究发现该基因单核苷酸多态性（SNP）与GDM发病风险相关联，但该基因DNA甲基化及二者间交互作用与GDM发病的关系有待阐明。本研究拟采用巢式病例对照研究设计，检测北京汉族GDM和健康孕妇外周血中候选SNPs和DNA甲基化水平，采用多水平模型和限制性立方样条模型探讨KCNQ1基因SNPs和DNA甲基化水平与GDM及相关指标（空腹血糖、糖耐量试验1小时和2小时血糖、胰岛素抵抗指数）的关联；采用条件Logistic回归和多因子降维法评价KCNQ1基因SNPs-DNA甲基化、SNPs-DNA甲基化-环境因素（孕前肥胖、孕期增重、饮食、体力活动）在GDM发病中的交互作用。本研究将为揭示KCNQ1基因在GDM发病中的作用机制和制定个体化防治策略提供依据。

Gestational diabetes mellitus (GDM) has become a public health problem endangering the short- and long-term health of mothers and infants. KCNQ1 gene is closely related to abnormal insulin secretion and insulin resistance, the pathophysiological basis of GDM. Our previous study found that single nucleotide polymorphism (SNP) of KCNQ1 gene was associated with the risk of GDM, but the effect of DNA methylation of KCNQ1 gene and the interaction between SNPs and DNA methylation on the risk of GDM is not clear. Based on the nested case-control study design, this study will recruit women with GDM and healthy pregnant women of Beijing Han descent from the established study cohort. Genotyping of candidate SNPs and quantifying of DNA methylation from peripheral blood DNA will be performed. Multilevel models and restricted cubic spline models will be used to explore the association of KCNQ1 gene SNPs and DNA methylation levels with the risk of GDM and related indicators (fasting glucose, 1-hour and 2-hour glucose of oral glucose tolerance test, insulin resistance index); conditional logistic regression models and generalized multifactor dimensionality reduction will be used to evaluate the interaction between KCNQ1 gene SNPs and DNA methylation, and between KCNQ1 gene SNPs, DNA methylation and environmental factors (prepregnancy obesity, gestational weight gain, dietary factors, physical activity) with the risk of GDM. This study will provide evidence for revealing the pathogenic mechanism of KCNQ1 gene on GDM and developing individualized intervention plans.