The Inflammatory Response Pathway in the Etiology of Polycystic Ovary Syndrome

描述(申请人提供)：多囊卵巢综合征(PCOS)是年轻女性最常见的内分泌疾病，在西方社会约7%的育龄妇女受到影响。它的特点是高雄激素血症和月经不调。除了这些生殖表型外，PCOS还与肥胖、胰岛素抵抗和患2型糖尿病(T2 DM)的风险增加有关。PCOS是可遗传的，与胰岛素抵抗、糖尿病和肥胖症有许多共同特征，这表明PCOS和T2 DM的遗传基础可能是相关的，甚至是相同的。越来越清楚的是，炎症反应的成员在包括糖尿病和肥胖症在内的代谢综合征的表型的病因学中起着重要作用。鉴于上述情况，我们将提出炎症反应基因的遗传变异与多囊卵巢综合征的病因有关的假说。我们建议通过在一组PCOS病例和对照中表征~30个炎症反应基因的变异来检验这一假设。我们的分析将分为三个具体目标。初步分析将包括一项关联性研究，在该研究中，我们测试了~43个候选基因内的单核苷酸多态(SNPs)与~1000名患有多囊卵巢综合征的女性和~1000名体重指数与种族匹配的对照组女性之间的关联。SNPs将覆盖每个基因的编码区和20kb的上下游，并将从HapMap项目中挑选出来，以获得最大的信息量。在Aim 2中，将通过对有希望的单倍型块进行深度测序和进一步的关联研究来识别潜在的功能变异，从而对有希望的基因/区域进行更详细的分析。目标3将检验假设，即在目标1+2中确定的基因的表达模式在多囊卵巢综合征中发生了改变。这些研究对于确定与多囊卵巢综合征的病因有关的基因以及在综合征中受到干扰的主要生物途径至关重要。此外，患有多囊卵巢综合征的女性患2型糖尿病的风险增加了7倍，这使得多囊卵巢综合征可能成为女性患2型糖尿病的主要风险因素。因此，阐明这些基因在PCOS病因学中的作用也应该有助于深入了解T2 DM的遗传学和病因学，从而可以在其他人群中进行测试。公共卫生相关性：多囊卵巢综合征(PCOS)是一种常见的内分泌疾病，以男性性激素升高和月经不调为特征，还与肥胖、胰岛素抵抗和患2型糖尿病(T2 DM)的风险增加7倍有关。由于炎症反应在代谢综合征、糖尿病和肥胖等与PCOS相关的疾病中起重要作用，我们假设炎症反应通路中的基因也参与了PCOS的发病，并建议测试~43个炎症反应基因在PCOS中的作用。这些研究将对识别导致多囊卵巢综合征(PCOS)病因学的基因至关重要，这是这种综合征中受到干扰的主要生物学途径，也可能为深入了解T2 DM的遗传学和病因学提供线索，T2 DM是西方社会日益常见的一种疾病。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of young women, affecting ~ 7 % of reproductive age women in western societies. It is characterized by hyperandrogenemia and menstrual irregularities. In addition to these reproductive phenotypes, PCOS is also associated with obesity, insulin resistance, and an increased risk of developing type 2 diabetes mellitus (T2DM). PCOS is heritable and shares many features in common with insulin resistance, diabetes and obesity, suggesting that the genetic underpinnings of PCOS and T2DM may be related or even identical. It is becoming increasingly clear that members of the inflammatory response are important in the etiology of phenotypes of the metabolic syndrome including diabetes and obesity. Given the above we will address the hypothesis that genetic variation in the inflammatory response genes contributes to the etiology of PCOS. We propose to test this hypothesis by characterizing variation in ~30 inflammatory response genes in a cohort of PCOS cases and controls. Our analysis will be divided into three Specific Aims. The initial analysis will consist of an association study in which we test for association between single nucleotide polymorphisms (SNPs) within ~43 candidate genes and ~1000 women with PCOS and ~1000 BMI and ethnicity matched control women. The SNPs will cover the coding region and 20 kb upstream and downstream of each gene and will be selected from the HAPMAP project for maximum informativeness. In Aim 2 promising genes/regions will be analyzed in greater detail by identifying potentially functional variants using deep sequencing of promising haplotype blocks and further association studies. Aim 3 will test the hypothesis that the expression pattern of the genes identified in Aims 1 + 2 is altered in PCOS. These studies will be critical in identifying genes that contribute to the etiology of PCOS and the primary biological pathways that are perturbed in the syndrome. Moreover, women with PCOS are at a seven-fold increased risk for developing T2DM making PCOS potentially the major risk factor for developing T2DM in women. Therefore, elucidating the role of these genes in the etiology of PCOS should also provide insight into the genetics and etiology of T2DM that can be tested in other populations. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is common endocrine disorder characterized by elevated male sex hormones and menstrual irregularities and is also associated with obesity, insulin resistance, and a 7 fold increased risk of developing type 2 diabetes mellitus (T2DM). Since the inflammatory response is important in disorders related to PCOS like the metabolic syndrome, diabetes and obesity, we hypothesize that genes in the inflammatory response pathway also contribute to PCOS and propose to test the role of ~43 inflammatory response genes in PCOS. These studies will be critical in identifying genes that contribute to the etiology of PCOS, the primary biological pathways that are perturbed in this syndrome, and potentially also provide insight into the genetics and etiology of T2DM, an increasingly common disorder in western societies.