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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 多囊卵巢综合征（PCOS）是影响6-7％的生殖妇女的内分泌疾病。患有PCOS的女性具有卵巢功能障碍，导致雄性激素水平升高（雄激素）。作为长期后果，它们可能发展不育症，2型糖尿病（DM），子宫子宫内膜癌和心血管疾病（CVD）。国家卫生研究院（NIH）在1990年定义了PCOS的诊断标准，包括：1）升高雄激素的临床和/或生化证据，2）长期缺乏排卵，3）排除相似的相关疾病。 PCOS被遗传为一种复杂的遗传疾病，意味着可能涉及多个基因，这些基因可能相互相互作用和/或与环境元素相互作用。 30％-40％的姐妹和20％-30％的受影响妇女的母亲也患有PCOS。但是，负责任基因或基因的鉴定很困难。迄今为止，PCOS的分子遗传研究仅限于研究候选基因的研究。这些研究集中在可能解释PCOS特征（例如胰岛素分泌和作用或肥胖症）的基因上。 药物遗传学涉及对改变对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中，几乎没有工作。胰岛素抵抗是PCOS的一个相关因素，表明需要一些胰岛素抵抗药物遗传学研究。二甲双胍是目前正在广泛临床用途的药物，是对PCOS治疗的最详尽研究。 越来越多的证据表明，遗传变异是通过相关多态性或DNA序列中的常见变异（称为单倍型）最好描述的。单倍型反映了全球基因结构，包括染色体块，这些染色体块在基因的人群史上一直没有重组。因此，我们计划使用单倍型来揭示候选基因中特定变体与二甲双胍治疗的反应之间的关系。 IRB的现有DNA样品和细胞系批准了＃3786，乳制品研究所AMP；营养流行病学，高加索人群将用于识别本研究中要对单倍型进行基因型的关键单核苷酸多态性（SNP）位点。 目前，这项研究是在少数受试者中进行的，以证明我们执行协议的能力。这项试验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研究。