THE GENETIC INHERITANCE OF POLYCYSTIC OVARY SYNDROME

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：量化与多囊卵巢综合征(PCOS)、糖尿病和肥胖症相关的特定DNA多态在PCOS妇女、PCOS妇女家庭成员和对照组(非PCOS妇女)中的患病率。 设计：前瞻性病例对照研究 研究计划：参与者包括年龄在18-39岁之间、因闭经/月经过少(10次/年)和无多毛而被诊断为多囊卵巢综合征的女性。 参与者将使用修改后的费里曼-加尔韦调查完成对头发模式的简短评估。他们将测量血压、脉搏、身高和体重。禁食10小时后，受试者将抽取大约30毫升的血液进行荷尔蒙水平和多态研究。将对血清样本进行以下分析：血糖、糖化血红蛋白、血细胞计数、肝功能测试、血脂和促甲状腺激素。血清样本将被冷冻和储存用于下列(当资金可用时)：总的和游离的睾酮、孕酮、催乳素、硫酸二氢表雄酮(DHEAS)、17-羟孕酮、黄体生成素、卵泡刺激素、胰岛素、组织纤溶酶原激活物(t-PA)、纤溶酶原激活物抑制物1(PAI-1)。荷尔蒙将只在生育年龄的女性身上使用。调查问卷、实验室结果和头发调查将被用来确定一个人是否患有多囊卵巢综合征。 用于聚合酶链式反应的全血将被收集在EDTA中，并在零下20摄氏度冷冻和储存。候选基因将从那些已经(或未来被鉴定)与多囊卵巢综合征、肥胖症或糖尿病相关的基因中选择(如β3肾上腺素能受体、肿瘤坏死因子-α和胰岛素受体基因VNTR)。DNA将使用一种商用试剂盒进行分离。我们将用聚合酶链式反应(PCR)分离和扩增特定的感兴趣基因。聚合酶链式反应产物将与感兴趣部位的特定限制性内切酶孵育。消化后的DNA片段将在2.5%的琼脂糖凝胶上运行，用溴化乙锭染色，并在紫外光下进行分析。 在多囊卵巢综合征组、家族成员组和对照组中，将报告特定多态的发生率。 临床意义：多囊卵巢综合征和糖尿病一样，表现出遗传暗示的遗传联系。基因使个体处于不同程度的胰岛素抵抗、多囊卵巢综合征、2型糖尿病，甚至特定终末器官损伤的风险中。确定与多囊卵巢综合征和胰岛素抵抗相关的不同基因多态是有价值的，因为它可以预测患者的疾病进展或对治疗的反应。 特定的多态将与种族、体重指数和实验室资料相关联，以表征和进一步定义多囊卵巢综合征的特定亚群。未来的治疗将针对这些亚群，以提高疗效。

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. OBJECTIVE: Quantify the prevalence of specific DNA polymorphisms associated with polycystic ovary syndrome (PCOS), diabetes, and obesity in women with PCOS, family members of women with PCOS, and controls (women without PCOS). DESIGN: Prospective case-control RESEARCH PLAN: Participants include women aged 18-39 with a diagnosis of PCOS based upon amenorrhea/oligomenorrhea (10/year) and no hirsutism. Participants will complete a brief assessment of hair patterns using the modified Ferriman-Gallwey survey. They will have blood pressure, pulse, height, and weight measured. After fasting for 10 hours, subjects will have approximately 30 cc of blood drawn for hormonal levels and polymorphism studies. Serum samples will be analyzed for the following: glucose, HbA1C, CBC, liver function tests, lipids, and TSH. Serum samples will be frozen and stored for the following (when funding becomes available): total and free testosterone, progesterone, prolactin, dihydoepiandrostendione sulfate (DHEAS), 17-hydroxyprogesterone, LH, FSH, insulin, tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1). Hormones will be run on reproductive-aged females only. Questionnaire, lab results, and hair survey will be used to determine if a person has PCOS. Whole blood for PCR will be collected in EDTA and frozen and stored at -20 degrees C. Candidate genes will be chosen from those which have been associated (or are identified in the future) with PCOS, obesity, or diabetes (such as the Beta 3 adrenergic receptor, TNF-Alpha, and insulin receptor gene VNTR). DNA will be isolated using a commercially available kit. Specific genes of interest will be isolated and amplified with polymerase chain reaction (PCR). PCR products will be incubated with specific restriction enzymes for sites of interest. Resulting digested DNA fragments will be run on a 2.5% agarose gel, stained with ethidium bromide, and analyzed under ultraviolet light. Occurrence rates of specific polymorphisms will be reported in the PCOS groups, family member group, and control group. CLINICAL RELEVANCE: PCOS, like diabetes, displays an inheritance suggestive of a genetic linkage. Genes place individuals at varying degrees of risk for insulin resistance, PCOS, type 2 diabetes, and even specific end organ damage. Determining distinct polymorphisms associated with PCOS and insulin resistance in valuable because it may predict a patient's disease progression or response to treatment. Specific polymorphisms will be correlated with ethnicity, BMI, and laboratory profiles to characterized and further define specific subsets within PCOS. Future treatments will be targeted to these subsets to improve efficacy.