PHARMACOGENETICS OF INSULIN RESISTANCE IN PCOS

PCOS 胰岛素抵抗的药物遗传学

• 批准号: 7606109
• 负责人: Ricardo Azziz
• 金额: $ 1.22万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606109
• 关键词: Accounting; Affect; Age; Androgens; Biochemical; Candidate Disease Gene; Cardiovascular Diseases; Caucasians; Caucasoid Race; Cell Line; Chronic; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Sequence; Diagnostic; Disease; Elements; Endocrine System Diseases; Endometrial Carcinoma; Epidemiology; Exclusion; Functional disorder; Funding; Gene Structure; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genotype; Grant; Haplotypes; Hereditary Disease; Hormones; Infertility; Inherited; Institution; Insulin; Insulin Resistance; Investigation; Metformin; Molecular Genetics; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Ovary; Ovulation; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Pilot Projects; Polycystic Ovary Syndrome; Population; Protocols documentation; Recording of previous events; Research; Research Ethics Committees; Research Institute; Research Personnel; Resources; Sampling; Single Nucleotide Polymorphism; Sister; Site; Source; Time Study; United States National Institutes of Health; Variant; Woman; Work; genetic variant; insulin secretion; male; nutrition; reproductive; response; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polycystic Ovary Syndrome (PCOS) is a endocrine disorder affecting 6-7% of reproductive-aged women. Women with PCOS have dysfunction of the ovaries that leads to elevated levels of male hormones (androgens). As long-term consequences they may develop infertility, type 2 diabetes mellitus (DM), uterine endometrial cancer, and cardiovascular disease (CVD). Diagnostic criteria for PCOS was defined in 1990 by the National Institutes of Health (NIH) to consist of: 1) clinical and/or biochemical evidence of elevated androgens, 2) chronic lack of ovulation, and 3) exclusion of similar related disorders. PCOS is inherited as a complex genetic disorder meaning that more than one gene may be involved, that the genes may interact with each other and/or with environmental elements. 30%-40% of sisters and 20%-30% of mothers of affected women also have PCOS. However, the identification of the responsible gene or genes has been difficult. The molecular genetic studies of PCOS have thus far been limited to investigations of candidate genes. These studies have focused on genes that may account for particular features of PCOS such as insulin secretion and action or obesity. Pharmacogenetics involves the study of genetic variants that alter response to drug therapy. There has been little work in the pharmacogenetics of insulin action and insulin resistance. Insulin resistance is an associated factor in PCOS indicating a need for some insulin resistance pharmacogenetic studies. Metformin is the drug currently in widespread clinical use and the most throughly investigated for treatment of PCOS. There is increasing evidence that genetic variation is best described by groups of associated polymorphisms or common variations in DNA sequence, referred to as haplotypes. Haplotypes reflect global gene structure, encompassing chromosomal blocks that have remained unbroken by recombination during the population history of the gene. Because of this we plan to use haplotypes as a means to uncover the relation between specific variants in candidate genes and the response to metformin therapy. Existing DNA samples and cell lines from IRB approved #3786, Dairy Research Institute for Genetics amp; Nutrition Epidemiology, Caucasian population will be used to identify the key single nucleotide polymorphism (SNP) sites for the haplotypes to be genotyped in this study. At this time, this study is being conducted in a small number of subjects to demonstrate our ability to carry out the protocol. Success in this pilot study will increase our ability to achieve funding from the NIH which will allow us to begin the full scale study.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 多囊卵巢综合症 (PCOS) 是一种内分泌疾病，影响 6-7% 的育龄妇女。患有多囊卵巢综合症的女性卵巢功能障碍，导致雄性激素（雄激素）水平升高。作为长期后果，他们可能会出现不孕、2 型糖尿病 (DM)、子宫内膜癌和心血管疾病 (CVD)。美国国立卫生研究院 (NIH) 于 1990 年定义了 PCOS 的诊断标准，包括：1) 雄激素升高的临床和/或生化证据，2) 长期缺乏排卵，以及 3) 排除类似的相关疾病。 多囊卵巢综合症是一种复杂的遗传性疾病，这意味着可能涉及多个基因，这些基因可能彼此相互作用和/或与环境因素相互作用。受影响女性的 30%-40% 的姐妹和 20%-30% 的母亲也患有 PCOS。然而，鉴定一个或多个负责基因一直很困难。迄今为止，多囊卵巢综合征的分子遗传学研究仅限于候选基因的研究。这些研究重点关注可能解释多囊卵巢综合症特定特征的基因，例如胰岛素分泌和作用或肥胖。 药物遗传学涉及改变药物治疗反应的遗传变异的研究。在胰岛素作用和胰岛素抵抗的药物遗传学方面的研究很少。胰岛素抵抗是 PCOS 的一个相关因素，表明需要进行一些胰岛素抵抗药物遗传学研究。二甲双胍是目前临床广泛使用的药物，也是治疗多囊卵巢综合征研究最深入的药物。 越来越多的证据表明，遗传变异最好由一组相关的多态性或 DNA 序列的常见变异（称为单倍型）来描述。单倍型反映了整体基因结构，包括在基因群体历史中未被重组破坏的染色体块。因此，我们计划使用单倍型作为揭示候选基因中特定变异与二甲双胍治疗反应之间关系的手段。 来自 IRB 的现有 DNA 样本和细胞系已获得批准 #3786，乳制品遗传学研究所营养流行病学，白种人群体将用于确定本研究中要进行基因分型的单倍型的关键单核苷酸多态性 (SNP) 位点。 目前，这项研究正在少数受试者中进行，以证明我们执行该方案的能力。这项试点研究的成功将提高我们从 NIH 获得资金的能力，这将使我们能够开始全面的研究。