PHARMACOGENETICS OF INSULIN RESISTANCE IN PCOS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 多囊卵巢综合征（PCOS）是一种内分泌失调，影响6-7%的育龄妇女。患有PCOS的女性卵巢功能障碍，导致男性激素（雄激素）水平升高。作为长期后果，他们可能发展为不孕症、2型糖尿病（DM）、子宫内膜癌和心血管疾病（CVD）。PCOS的诊断标准由美国国立卫生研究院（NIH）于1990年定义，包括：1）雄激素升高的临床和/或生化证据，2）长期缺乏排卵，3）排除类似的相关疾病。 PCOS是一种复杂的遗传性疾病，这意味着可能涉及多个基因，这些基因可能相互作用和/或与环境因素相互作用。30%-40%的姐妹篇和20%-30%的受影响妇女的母亲也患有PCOS。然而，鉴定一个或多个负责基因是困难的。PCOS的分子遗传学研究迄今仅限于候选基因的研究。这些研究集中在可能导致PCOS特定特征的基因上，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工作很少。胰岛素抵抗是多囊卵巢综合征的一个相关因素，提示有必要进行胰岛素抵抗的遗传药理学研究。二甲双胍是目前临床上广泛使用的药物，也是治疗PCOS最彻底的药物。 越来越多的证据表明，遗传变异最好用DNA序列中相关多态性或常见变异的组来描述，称为单倍型。单倍型反映了整体基因结构，包括在基因的群体历史中通过重组保持未断裂的染色体块。正因为如此，我们计划使用单倍型作为一种手段来揭示候选基因中的特定变异与二甲双胍治疗反应之间的关系。 将使用来自IRB批准的#3786（奶牛遗传与营养流行病学研究所，高加索人群）的现有DNA样本和细胞系来鉴定本研究中待基因分型单倍型的关键单核苷酸多态性（SNP）位点。 目前，本研究正在少数受试者中进行，以证明我们执行方案的能力。这项试点研究的成功将增加我们从NIH获得资金的能力，这将使我们能够开始全面的研究。

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.