压力性尿失禁的遗传易感基因与雌二醇的交互作用及其机制研究

Stress urinary incontinence (SUI) has become a social disease which seriously affected the physical and mental health of the middle-aged and elderly women and their life quality in China, and it imposes a heavy financial burden on individuals, families and society. The etiology of SUI is complex and poorly understood yet. Therefore, the research which focuses on the susceptibility to SUI is very urgent and of great significance. To clarify the role of estradiol in the development of SUI, and to identify the susceptibility genes and loci of SUI, our study aims to investigate the relationship between serum estradiol level and susceptibility to SUI, and to explore the association of candidate loci in TGFB1, SMAD2 gene which involved in TGF-β1/Smad signaling pathways with the risk of SUI. Furthermore, we will explore the interaction of estradiol and these genes and its influences on the risk degree and mechanism of susceptibility to SUI. Based on the findings obtained by related literatures, combining field research with experimental research, this study intends to adopt a case-control study to achieve above goals. The results of this study will be of great help to further understand the etiology and molecular mechanisms underlying SUI, and to reveal the potential therapeutic targets of SUI. Intervention strategies will be made based on the research results to decrease the incidence of SUI. In conclusion, this study is of great importance to the prevention of SUI and the promotion of Healthy China.

压力性尿失禁（SUI）已成为一种严重影响我国中老年妇女身心健康和生活质量的社会性疾病，给个人、家庭及社会造成沉重的经济负担。SUI病因复杂，至今尚不十分明确 。因此，开展SUI的易感性研究十分重要和紧迫。本研究拟结合相关文献报道，以现场研究和实验研究相结合，采用病例-对照研究方法，探讨血清中雌二醇水平与SUI易感性的关系，明确雌二醇在SUI发生发展中的作用；探讨TGF-β1/Smad信号通路中TGFB1、SMAD2基因候选位点与SUI发生风险间的关系，识别SUI的遗传易感基因及位点；在此基础上，探索雌二醇和遗传易感基因的交互作用及其对SUI易感性的作用及机制。通过本研究，进一步明确SUI的病因和发病的分子机制，揭示SUI的潜在治疗靶点，从而提出干预策略，切实降低我国妇女SUI的发病率。本研究结果对SUI的防治和促进健康中国均具有重要意义。

压力性尿失禁（Stress Urinary Incontinence, SUI）是指在咳嗽或喷嚏等腹压增加时出现不自主的尿液自尿道外口渗漏，是一种影响中老年妇女健康的常见疾病。SUI 病因复杂，至今尚不十分明确。本研究采用病例对照的研究设计，以 493例SUI和499例对照为研究对象，运用现场流行病学方法调查SUI的影响因素；采用化学发光微粒子免疫检测法检测病例组与对照组血清雌二醇水平，分析两组间的差异；采用全外显子组测序技术检测TGFβ1/SMAD通路中重要基因上的罕见遗传变异与 SUI 发病的关系，分析常见遗传变异与SUI发病的关联性。本研究发现，BMI（OR = 1.110, 95%CI: 1.056-1.167; P < 0.001）、经阴道分娩次数（OR = 1.645, 95%CI: 1.430-1.893; P < 0.001）、高血压史（OR = 2.742, 95%CI: 1.379-5.454, P = 0.004）和盆腹腔手术史（OR = 3.252, 95%CI: 1.728-6.120; P < 0.001）是SUI发病的独立影响因素。血清雌二醇水平< 10 pg/mL与绝经后女性SUI的发病风险呈显著正相关（OR: 2.55, 95%CI: 1.19 - 5.48; P = 0.016），血清雌二醇水平低（<10 pg/mL）是绝经后妇女SUI发病的危险因素。TGFβ1/SMAD通路中4个基因突变可能是SUI的遗传易感位点，分别为TGFBR2基因上的rs200111443、SMAD3基因上的rs184408275、SMAD7基因上的rs1318674011、TGFB1基因上的rss569594975；常见变异位点GLYATL3（rs9367359）可能与SUI的发病相关。未发现GLYATL3（rs9367359）与血清雌二醇在影响SUI发生发展中具有交互作用。本研究识别了影响SUI发生的关键因素及其风险程度，为提出有效的和有针对性的 SUI 防治措施和干预策略提供了参考和依据；明确了血清雌二醇水平在绝经后妇女SUI发生发展中的作用，丰富了对 SUI 病因学的认识，为雌激素疗法在绝经后妇女SUI治疗中的应用提供了新的参考；识别了SUI的关键遗传易感位点，为揭示SUI发病的分子机制提供了新的线索。