Genetics of Insulin Resistance in PCOS: The PPAR Pathway

描述（由申请人提供）：多囊卵巢综合征（PCOS）是一种异质性疾病，以慢性无排卵、高雄激素和胰岛素抵抗为特征，估计在所有女性中患病率为5-10%。家族研究表明多囊卵巢综合征的遗传易感性和几个候选多囊卵巢综合征易感基因已被探索。到目前为止，家谱研究主要集中在女性的类固醇途径功能障碍上，在确定多囊卵巢综合征的遗传基础方面收效甚微。最近的假设是胰岛素抵抗，而不是雄激素过多，是多囊卵巢综合征的中心缺陷。过氧化物酶体增殖物激活受体γ (PPAR [γ])已被认为是2型糖尿病胰岛素抵抗的潜在候选基因。迄今为止还没有针对PPAR的研究。PCOS先证者及其家族成员胰岛素抵抗与胰岛素通路的关系。鉴于多囊卵巢综合征的高患病率及其与冠心病的相关性，多囊卵巢综合征可能是冠心病（CHD）高危女性中最大的、独特的群体。因此，了解多囊卵巢综合征的病因可能对妇女的公共卫生有很大的影响。本初步研究将通过使用参数和非参数方法分析5个多代多复合家族（N= 125）的连锁关系来检查扩展谱系。我们将通过以下具体目标探索遗传机制：(1)证明我们有能力登记PCOS先显子及其多代多重家族成员，研究PCOS家族中的胰岛素抵抗标记；(2)对5个先显子及其多代多重家族成员进行基因分型，检测候选基因P12A和IRS-1或其附近的单核苷酸多态性（snp）以及候选基因脂蛋白脂肪酶和乙酰辅酶a羧化酶附近的微卫星标记，以检测PCOS与这些候选基因的连锁关系。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic anovulation, hyperandrogenism, and insulin resistance with an estimated prevalence of 5-10% among all women. Family studies have indicated a genetic predisposition to the development of PCOS and several candidate PCOS susceptibility genes have been explored. Thus far, pedigree studies have mainly focused on steroidogenic pathway dysfunction in women with little success in determining a genetic basis for PCOS. It has more recently been postulated that insulin resistance, rather than hyperandrogenism, is the central defect in PCOS. Peroxisome proliferator-activated receptor gamma (PPAR [gamma]) has been indicated as a potential candidate gene for insulin resistance in Type 2 diabetes. No studies to date have focused on the PPAR. pathway and insulin resistance in PCOS probands and their family members. Given the high prevalence of PCOS and its association with coronary heart disease, PCOS may represent the largest, unique group of women at high-risk for the development of coronary heart disease (CHD). Thus understanding the etiology of PCOS may have a large public health impact for women. This pilot study will examine extended pedigrees by analyzing linkage using both parametric and non-parametric methods in five multigeneration, multiplex families (N= 125). We will explore genetic mechanisms through the following specific aims by: (1) demonstrating our ability to enroll both PCOS probands and their multi generation, multiplex family members to study insulin resistance markers in families with PCOS and (2) genotyping five probands and their multigeneration, multiplex family members for single nucteotide polymorphisms (SNPs) at or near candidate genes P12A and IRS-1 and microsatellite markers near candidate genes lipoprotein lipase and acetyI-CoA carboxylase, to test for linkage of PCOS with these candidate genes.