胰岛素抵抗相关基因罕见遗传变异与多囊卵巢综合征的关联研究

项目名称： 胰岛素抵抗相关基因罕见遗传变异与多囊卵巢综合征的关联研究

项目编号： No.81501231

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李淑元

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 多囊卵巢综合征（PCOS）是育龄妇女常见的生殖内分泌系统疾病，不但导致不孕，而且相应个体罹患糖尿病和心血管疾病的风险亦增加。PCOS是高度遗传的复杂疾病（遗传贡献约70%），虽经多年研究，但所发现的遗传易感位点远不足以解释其遗传度，存在遗传度丢失。我们推测之前研究策略未能系统检测的罕见变异是造成PCOS遗传度丢失的主要原因之一。为验证这一假设，我们拟选择PCOS病理生理机制中的关键环节——“胰岛素抵抗”的相关基因（约200个），依托新一代测序平台，在150例PCOS病例及150例对照中对这些基因的功能区段进行深度测序（总长度约800kb/个体，拟测序深度100×），并结合生物信息学手段，探索目标区段内同PCOS相关的功能性罕见变异，并分析罕见变异同PCOS生殖内分泌、代谢表型的关联，以期阐明罕见变异在PCOS发病中的作用，为今后深入研究PCOS的发病机理以及药物靶点的开发提供依据及思路。

中文关键词： 多囊卵巢综合征；胰岛素抵抗；新一代测序；罕见变异

英文摘要： Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of reproductive age. In addition to its reproductive features, such as reduced fertility, PCOS also has numerous metabolic consequences, including increased risk of type 2 diabetes mellitus and cardiovascular disease. Although PCOS is a complex disease with a heritability of approximately 70%, most genetic variants identified so far confer relatively small increments in risk, leading to missing heritability. We suppose that the major causes of missing heritability of PCOS are caused by rare variants, which are not tested systematically in previous studies. To test this hypothesis, deep resequencing of functional regions of about 200 genes in the insulin resistance pathway, about 800 kb per individual, will be conducted in 150 PCOS cases and 150 healthy controls to screen the full set of variants systematically using next-generation sequencing platform with the coverage of 100×. Further study combined with bioinformatics methods will be used to explore the association of the rare variants in the target genes with PCOS, endocrine and metabolic phenotype, and clarify the role of rare variants in the pathogenesis of PCOS. Our study will provide insights into the pathogenesis of PCOS and the development of new drug targets.

英文关键词： polycystic ovary syndrome;insulin resistance;next generation sequencing;rare mutation