Genetics of IR 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，其特征为慢性无排卵、高雄激素血症和胰岛素抵抗，在所有女性中的估计患病率为5-10%。家族研究表明，遗传易感性的发展PCOS和几个候选PCOS易感基因已被探索。到目前为止，系谱研究主要集中在女性类固醇生成途径功能障碍，在确定PCOS的遗传基础方面几乎没有成功。最近有人推测胰岛素抵抗，而不是高雄激素血症，是PCOS的核心缺陷。过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体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，还没有研究关注过PPAR。途径与胰岛素抵抗的关系。鉴于PCOS的高患病率及其与冠心病的相关性，PCOS可能代表了最大的，独特的女性群体，处于冠心病（CHD）的高风险发展中。因此，了解PCOS的病因可能对妇女的公共卫生产生重大影响。这项试点研究将检查扩展家系分析连锁使用参数和非参数方法在五个多代，多重家庭（N= 125）。我们将通过以下具体目标探索遗传机制：（1）证明我们有能力招募PCOS先证者及其多代、多家族成员，以研究PCOS家族中的胰岛素抵抗标志物，和（2）对5名先证者及其多代进行基因分型，在候选基因P12 A和IRS处或附近的单核苷酸多态性（SNP）的多重家族成员-1和候选基因脂蛋白脂酶和乙酰辅酶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。

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.