5-HT调控系统相关基因多态性与原发性早泄及其个体化药物治疗的相关性研究

Lifelong premature ejaculation (LPE), with high incidence rate, has much serious impact on psychosomatic health of both men and women, and its etiology and the mechanism of individual differences in the treatment of LPE is not clear. 5-HT control system has been confirmed to play an important role in the pathogenesis of LPE, and there are many gene polymorphisms of 5-HT synthesis enzyme (TPH), receptors (5-HT1A and 5-HT2C) and serotonin transporter (5-HTT) in this 5-HT control system, and also these gene polymorphisms in this 5-HT control system have been proved to affect the synthesis, transfer and uptake of 5-HT. Research on the correlation between the gene polymorphisms of this system and LPE is poorly understood, and there are many deficiencies, such as only observing one indicator, only detecting one gene polymorphism, and only determining one regulatory factor in 5-HT control system, as well as the small sample size. Based on the above research background, this project will expand the sample size and observe a variety of indicators, and employ a case-control study and analysis of PCR-RLFP, to research the correlation between eight common polymorphisms of 5-HT synthesis enzyme (TPH), receptors (5-HT1A and 5-HT2C) and serotonin transporter (5-HTT) in 5-HT control system and the pathogenesis of LPE, as well as the correlation between this eight common polymorphisms and the individual differences of selective serotonin reuptake inhibitors (SSRIs) in the treatment of LPE, and as the same time to compare the interaction among these gene polymorphisms, and hence to further reveal in detail the association between the gene polymorphisms in 5-HT control system and LPE, so as to clear the pathogenesis of LPE and provide the better evidence-based medicine data about SSRIs individualized medicine therapy for LPE.

原发性早泄（LPE）发病率高，严重影响男女双方心身健康，而其病因及治疗的个体差异机制尚不清楚。5-HT调控系统在PE发病中起重要作用，而且该系统中5-HT合成限速酶（TPH）、受体（5-HT1A及5-HT2C）及转运体（5-HTT）存在多种基因多态性，影响该系统中5-HT的合成、传递及再摄取。有关该系统基因多态性与LPE之间相关性的研究甚少，且存在不足：仅观察一种指标，检测一种基因多态性，研究该系统中一种调控因素，并且样本量少。本课题在扩大样本量及观察多种指标的同时，采用病例对照研究及PCR-RLFP分析，通过研究5-HT调控系统TPH、5-HT1A及5-HT2C受体和5-HTT 中8种常见的基因多态性与LPE发病，以及药物治疗个体差异之间的相关性，并比较此8种基因多态性之间的交互作用，以进一步系统地揭示该系统基因多态性与LPE的关联性，为明确LPE的病因，以及其个体化药物治疗提供依据。

LPE是一种常见的性功能障碍，严重影响患者生活。5-HT及其受体神经传导减少是引起PE的重要因素。任何影响5-HT合成及转运的因素都将造成5-HT功能紊乱，从而影响射精功能。本研究通过测定5-HT、瘦素及叶酸水平，证实其在PE诊断中的临床价值；检测5-HT调控系统相关基因（5-HT转运体、5-HT合成限速酶、5-HT受体）及CYP24A1基因多态性分布，探索中国人群的LPE易感基因，揭示其危险因素和基因多态性的交互作用，及标签SNP和基因单倍体对LPE的遗传易感性，从基因多态性角度，探讨LPE的发病机制。结果：1. 早泄患者血浆瘦素比对照组明显偏高，而5-HT、叶酸明显偏低。2. SLC6A4编码的5-HTT-rs9303628等位基因T和基因型T/T和C/T-T/T与LPE发病风险降低显著相关；5-HTT-rs2054847等位基因T和基因型C/T-T/T与LPE发病风险降低显著相关；单倍型Ars9303628/Crs2054847与LPE发病风险降低显著相关。TPH2- rs11178996在等位基因模型下与LPE发病风险降低相关；与携带“A”等位基因相比，携带“G”等位基因个体发生PE的风险明显降低；单倍型Grs11179041/ Trs10879352可降低LPE发病风险。HTR1A-rs6295与LPE发病风险增加相关，GG基因型LPE发病风险比C/C-C/G基因型高3.44倍。CYP24A1-rs1570669等位基因A与LPE发病风险增加显著相关，且AA基因型与LPE发病风险增加显著相关，AA携带者LPE发病风险比GG携带者高2.26倍。除TPH2的基因多态性与瘦素、叶酸和5-HT水平显著相关外，5-HTT、5-HT受体及CYP24A1基因多态性均与瘦素、5-HT和叶酸水平无关。3. 5-HT调控系统相关基因及CYP24A1基因均未发现位点的基因型频率及基因型在有效组和无效组之间存在显著性差异。研究发现了中国汉族人群LPE的5-HT调控系统相关基因及CYP24A1基因SNPs分布情况及差异；较为全面阐明了5-HT调控系统相关基因及CYP24A1基因SNPs与LPE发病的相关性；不仅有利于探讨LPE发病机制，也为寻找新的LPE治疗靶点提供了科学依据；首次从遗传方面，揭示了中国汉族人群LPE的基因多态性变化的类型，对丰富我国生物资源基因库内涵具有重要意义。