Hot Flushes and SNPs of the Norepinephrine and Serotonin Transporter Genes

描述（由申请人提供）：围绝经期和绝经后期间的潮热造成了重大的公共卫生问题，因为它们（i）是妇女在绝经过渡期寻求医疗护理的主要原因;（ii）经常对妇女的生活质量产生负面影响，因为它们与抑郁、睡眠障碍有关，导致疲劳、易怒和健忘，以及严重的身体不适和对工作的负面影响;以及（iii）被认为是一些即将发生的严重情况的迹象。尽管潮热在女性生活中的重要性，但对潮热的潜在机制或风险因素知之甚少。虽然潮热最有效的治疗方法是雌激素替代疗法，但由于激素治疗的潜在风险，许多女性试图寻找替代疗法，如选择性5-羟色胺和/或去甲肾上腺素再摄取抑制剂（SSRIs/SNRIs），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灵敏度并随后影响潮热，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，但反应是异质的（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SSRIs/SNRIs没有反应。我们的假设是，异质性反应是由于单核苷酸多态性的5-羟色胺转运体（SERT）和/或去甲肾上腺素转运体（NET）基因。因此，我们提出了以下具体目标：（1）在前一个资助期招募的800名围绝经期妇女的样本中，对SERT和NET基因内的一组综合SNP进行基因分型，其中58%经历过潮热，并在招募的200名妇女的样本中对这些基因进行基因分型，（2）确定这些SNP是否与潮热相关。该提案符合R21的资金要求，因为它首次探索了SERT和NET基因的SNP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于这些SNP，那么定制的基于基因型的疗法可能是提高这种方法在没有激素的情况下治疗令人烦恼的潮热的疗效的最终解决方案。 公共卫生相关性：尽管围绝经期的潮热会引起重大的公共卫生问题。关于潮热的潜在机制知之甚少。许多妇女试图寻找替代疗法，雌激素，如选择性血清素和/或去甲肾上腺素再摄取抑制剂（SSRIs/SNRIs）。然而，这些反应是异质性的，可能是由于个体基因变异。本建议书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.