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）：绝经期和绝经后时期的热潮引起了一个重大的公共卫生问题，因为她们（i）是妇女在绝经期过渡期间寻求医疗服务的主要原因； （ii）通常会对女性的生活质量产生负面影响，因为她们与抑郁症相关，导致疲劳，易怒和健忘以及对工作的急性身体不适和负面影响； （iii）被认为表明了一些即将来临的严重条件。尽管热潮在女性的生活中很重要，但对基本机制或热潮的危险因素知之甚少。尽管最有效的潮红疗法是雌激素替代疗法，但由于激素疗法涉及的潜在风险，许多妇女试图找到替代性疗法，例如选择性的5-羟色胺和/或5-羟色胺 - 甲肾上腺素肾上腺素的抑制剂（SSSRIS/SNRIS），以及与Clonidinidine相比，并将其降低了。 治疗。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，然后影响热水液，在温度调节中起关键作用。尽管围绝经妇女的亚群确实对SSRIS/NRIS做出了反应，但反应是异质的（有些人反应良好，有些人根本没有反应）。该应用程序的总体目标是探讨为什么一些有热潮的女性对SSRIS/SNRIS不反应。我们的假设是，异基因反应是由于5-羟色胺转运蛋白（SERT）和/或去甲肾上腺素转运蛋白（NET）基因的单核苷酸多态性引起的。因此，我们提出了以下具体目的：（1）基因型在SERT和净基因中的一组全面的SNP和净基因样本中的800个perimenobausal妇女样本中，在先前的资金期间招募了招募，其中58％的人经历了200名妇女的样本中的热水冲洗和基因类型，并且（2）是否招募了这些SNP的样本，并且（2）确定这些SNP是否与这些SNP相应。该提案与R21的资金要求相匹配，因为它首次探讨了SERT SENP和净基因之间的关系，作为潮热缓解的预测指标。如果对SSRI/SNRI疗法的异质反应是由于这些SNP引起的，那么一种定制的基于基因型的治疗可能是提高这种方法治疗无激素的混杂热冲洗方法的最终解决方案。 公共卫生相关性：尽管围绝经期间的热潮构成了重大的公共卫生问题。关于潮热的基本机制知之甚少。许多女性试图找到替代疗法，例如选择性5-羟色胺和/或5-羟色胺 - 肾上腺素再摄取抑制剂（SSRIS/SNRIS）。但是，对它们的反应是异质的，可能是由于个体基因的变异。该建议将确定这些变化及其与热潮的关系。