Hot Flushes and SNPs of the Norepinephrine and Serotonin Transporter Genes

潮热以及去甲肾上腺素和血清素转运蛋白基因的 SNP

• 批准号: 7990619
• 负责人: ISTVAN Jozsef MERCHENTHALER
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990619
• 关键词: Acute; Affect; Alternative Therapies; Body Temperature; CYP1B1 gene; Caring; Clinical; Clonidine; Data; Estradiol; Estrogen Replacement Therapy; Estrogens; Estrone; Fatigue; Funding; Genes; Genetic Polymorphism; Genotype; Goals; Gold; Heating; Hormones; Hot flushes; Hypothalamic structure; Individual; Life; Medical; Menopause; Mental Depression; Neurons; Neurotransmitters; Norepinephrine; Obesity; Perimenopause; Physiologic Thermoregulation; Play; Postmenopause; Pre-Clinical Model; Public Health; Quality of life; Recruitment Activity; Reporting; Risk; Risk Factors; Role; Sampling; Serotonin; Serum; Single Nucleotide Polymorphism; Sleep disturbances; Solutions; Sweat; Sweating; Sympathetic Nervous System; Symptoms; Time; Variant; Vasodilation; Woman; Work; base; cigarette smoking; comparative efficacy; experience; hormone therapy; inhibitor/antagonist; innovation; medical attention; noradrenaline transporter; pre-clinical; response; reuptake; serotonin transporter

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.

描述（由申请人提供）：围绝经期和绝经后期间的潮热构成了重大的公共卫生问题，因为它们 (i) 是女性在绝经过渡期间寻求医疗护理的主要原因； (ii) 常常对妇女的生活质量产生负面影响，因为它们与抑郁、睡眠障碍导致疲劳、易怒和健忘以及急性身体不适和对工作的负面影响有关； (iii) 被认为预示着一些即将发生的严重情况。尽管潮热在女性的生活中很重要，但人们对潮热的潜在机制或危险因素知之甚少。虽然潮热最有效的治疗方法是雌激素替代疗法，但由于激素治疗存在潜在风险，许多女性尝试寻找替代疗法，例如选择性血清素和/或血清素-去甲肾上腺素再摄取抑制剂（SSRIs/SNRIs），可乐定和加巴喷丁尽管与雌激素替代疗法相比疗效较低。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，在体温调节中发挥着关键作用。尽管围绝经期妇女的一个亚群确实对 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）。该应用的总体目标是探索为什么一些潮热女性对 SSRIs/SNRIs 没有反应。我们的假设是异质反应是由于血清素转运蛋白（SERT）和/或去甲肾上腺素转运蛋白（NET）基因的单核苷酸多态性造成的。因此，我们提出以下具体目标：（1）在上一个资助期间招募的 800 名围绝经期女性样本中，对 SERT 和 NET 基因内的一组全面的 SNP 进行基因分型，其中 58% 的女性经历过潮热，并对这些基因进行基因分型招募 200 名女性样本，(2) 确定这些 SNP 是否与潮热相关。该提案符合 R21 的资助要求，因为它首次探讨了 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 疗法的异质反应是由这些 SNP 引起的，那么基于基因型的定制疗法可能是提高这种无需激素治疗烦人的潮热方法的疗效的最终解决方案。 公共健康相关性：尽管围绝经期期间的潮热引起了重大的公共健康问题。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，例如选择性血清素和/或血清素-去甲肾上腺素再摄取抑制剂（SSRIs/SNRIs）。然而，对这些的反应是异质的，可能是由于个体基因变异所致。该提案将确定这些变化及其与潮热的关系。