Hot Flushes and SNPs of the Norepinephrine and Serotonin Transporter Genes

描述(申请人提供)：围绝经期和绝经后潮热对公共卫生构成重大担忧，因为它们(I)是妇女在更年期过渡期间寻求医疗护理的主要原因；(Ii)通常负面影响妇女的生活质量，因为它们与抑郁症、导致疲劳、易怒和健忘的睡眠障碍以及急性身体不适和对工作的负面影响有关；(Iii)被认为是一些迫在眉睫的严重疾病的预兆。尽管潮热在女性生活中很重要，但人们对潮热的潜在机制或风险因素知之甚少。虽然治疗潮热最有效的疗法是雌激素替代疗法，但由于激素疗法涉及的潜在风险，许多女性试图寻找替代疗法，如选择性5-羟色胺和/或5-羟色胺-去甲肾上腺素再摄取抑制剂(SSRIs/SNRI)、可乐定和加巴喷丁，尽管它们的疗效低于雌激素替代疗法。临床和临床前数据确实表明，这些神经递质通过改变恒温器的敏感度，从而影响潮热，在体温调节中发挥关键作用。尽管围绝经期妇女的亚群确实对SSRIs/NRIs有反应，但这种反应是不同的(有些人反应良好，有些人根本没有反应)。这个应用程序的总体目标是探索为什么一些潮热的女性对SSRI/SNRI没有反应。我们的假设是，这种异源反应是由于5-羟色胺转运体(SERT)和/或去甲肾上腺素转运体(NET)基因的单核苷酸多态性所致。因此，我们提出了以下具体目标：(1)对800名围绝经期妇女(其中58%经历潮热)进行SERT和Net基因内一组全面的SNPs的基因分型，并在200名被招募的妇女样本中对这些基因进行基因分型；(2)确定这些SNPs是否与潮热有关。这项建议与R21的资金要求相匹配，因为它首次探索了SERT的SNPs和净基因之间的关系，作为潮热缓解的预测因子。如果对SSRI/SNRI疗法的异质性反应是由这些SNPs引起的，那么定制的、基于基因的疗法可能是提高这种方法在没有激素的情况下治疗烦人的潮热的有效性的最终解决方案。 公共卫生相关性：尽管围绝经期潮热是一个重大的公共卫生问题。人们对潮热的潜在机制知之甚少。许多女性试图寻找雌激素的替代疗法，如选择性5-羟色胺和/或5-羟色胺-去甲肾上腺素再摄取抑制剂(SSRIs/SNRI)。然而，对这些的反应是异质性的，可能是由于个体基因的差异。这项建议将确定这些变化及其与潮热的关系。

DESCRIPTION (provided by applicant): Hot flushes during the perimenopausal and post-menopausal periods pose a significant public health concern because they (i) are the primary reason that women seek medical care during the menopausal transition; (ii) often negatively impact the quality of life for women because they are associated with depression, sleep disturbances resulting in fatigue, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work; and (iii) are thought to be indicative of some impending, serious conditions. Despite the importance of hot flushes in a woman's life, little is known about the underlying mechanism or the risk factors for hot flushes. Although the most efficacious therapy for hot flushes is estrogen replacement therapy, due to the potential risks involved with hormone therapy, many women try to find alternative therapies, such as the selective serotonin and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), clonidine, and gabapentine in spite of their lower efficacy compared to estrogen replacement therapy. Clinical and preclinical data indeed show that these neurotransmitters play critical roles in thermoregulation by changing the sensitivity of the thermostat and subsequently, affecting hot flushes. Although a subpopulation of perimenopausal women do respond to SSRIs/NRIs, the response is heterogenous (some individuals respond well some do not respond at all). The overall goal of this application is to explore why some women with hot flushes do not respond to SSRIs/SNRIs. Our hypothesis is that the heterogenouos response is due to single nucleotide polymorphisms of the serotonin transporter (SERT) and/or the norepinephrine transporter (NET) genes. Therefore, we propose the following specific aims: (1) Genotype a comprehensive set of SNPs within the SERT and NET genes in a sample of 800 perimenopausal women recruited during a previous funding period and 58% of whom experienced hot flushes and genotype these genes in a sample of 200 women being recruited and (2) Determine whether these SNPs are correlated with hot flushes. This proposal matches the R21 funding requirements in that it explores, for the first time, the relationship between SNPs of SERT and NET genes as predictors of hot flush relief. If the heterogeneous response to SSRI/SNRI therapies is due to these SNPs, then a customized, genotype-based therapy may be the ultimate solution to increase efficacy of this approach to treating bothersome hot flushes without hormones. PUBLIC HEALTH RELEVANCE: Although hot flushes during the perimenopausal period pose a significant public health concern. Little is known about the underlying mechanism of hot flushes. Many women try to find alternative therapies, to estrogen such as the selective serotonin and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs). However, the response to these is heterogenous and might be due to individual gene variations. This proposal will identify these variations and their relationship to hot flushes.