肥胖及其风险基因多态性影响女童性早熟的机制研究

Precocious puberty is an important disease that threatens children’s health. Based on our previous findings, the prevalence of precocious puberty in obese girls was significantly higher than that of girls with normal weight, and we found by searching GWAS study catolog database that some genes of obesity and precocious puberty overlap. All of these suggest that the pleiotropic obesity gene may influence the currence of precocious puberty. The machanism of the effect of obesity gene polymorphism on precocious puberty remains unclear. By detecting the polymorphism of girls with normal control, simple obesity, precocious puberty combined with normal weight ,and precocious puberty combined with obesity, our goals are to explore: 1. the effect of gene polymorphism of obesity on precocious puberty;2.the changes of gene polymorphisms in girls with obesity and precocious puberty,3.direct effects of obesity on precocious puberty; 4.the metabolic pathway and function of obesity pleiotropic genes influencing precocious puberty. Based on the case-control study, a cohort study will be further conducted to confirm the research findings among 7-10 years old school girls. This study will be important in elucidating the genetic pathogenesis of precocious puberty, and our findings will provide scientific evidence for prevention and control of precocious puberty.

性早熟是威胁儿童健康的重要疾病。我们前期研究发现肥胖女童性早熟患病率明显高于正常体重女童，查询GWAS数据库发现肥胖和性早熟有部分基因重叠，提示肥胖可能通过多效性基因影响性早熟发生。目前肥胖基因多态性对女童性早熟的影响机制尚不清楚，本项目通过SNaPshot技术检测正常对照、单纯性肥胖、正常体重性早熟和肥胖合并性早熟4组女童的基因多态性，分别探讨：1.肥胖女童遗传风险和基因多态性对女童性早熟的影响；2.肥胖和性早熟中肥胖基因多态性的变化趋势；3.肥胖对女童性早熟的直接作用效应；4.肥胖多效性基因影响女童性早熟的调控通路和功能。在病例对照研究基础上，进一步在7-10岁学校女童中开展队列研究，验证肥胖及其风险基因多态性对性早熟的影响，进一步研究瘦素等基因通过KISS1/GRP54通路调控性早熟发生的功能机制。本研究有助于揭示肥胖风险基因多态性影响女童性早熟发生的机制，对性早熟防治具有重要意义。

性早熟是威胁儿童健康的重要疾病，影响儿童成年后的身高、心理和生殖功能等。我们前期研究发现肥胖女童性早熟患病率明显高于正常体重女童，查询GWAS数据库发现肥胖和性早熟有部分基因重叠，提示肥胖可能通过多效性基因影响性早熟发生。目前肥胖基因多态性对女童性早熟的影响机制尚不清楚.在病例对照研究基础上，本项目通过SNaPshot技术检测正常对照、单纯性肥胖、正常体重性早熟和肥胖合并性早熟4组女童的基因多态性，研究发现中国学校儿童在广东中山和山东曲阜两地学龄儿童中性早熟患病率较高，尤其是女童的性早熟患病率较高（中山11.47%，曲阜11.53%），在超重肥胖儿童中高于正常体重儿童；肥胖女童遗传风险基因MC4R rs571312多态性对女童性早熟具有明显影响，以等位基因关联分析中有统计学差异的4个位点（rs6752378, rs571312, rs12970134 and re29941）构建多基因风险评分（PRS），评估PRS与性早熟风险之间的关联，结果显示，PRS越高，发生性早熟的风险越大（P＜0.001）。进一步分析抗生素与性早熟之间的联系发现，抗生素暴露会增加性早熟的患病风险。本研究为控制超重肥胖对性早熟的影响提供科学证据，也从遗传和环境角度对性早熟的防控提供依据，对性早熟防治具有重要意义。