The Inflammatory Response Pathway in the Etiology of Polycystic Ovary Syndrome

描述（由申请人提供）：多囊卵巢综合征（PCOS）是年轻女性最常见的内分泌疾病，影响西方社会约7%的育龄妇女。其特征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2型糖尿病（T2DM）风险增加有关。多囊卵巢综合征是遗传性的，与胰岛素抵抗、糖尿病和肥胖有许多共同的特征，这表明多囊卵巢综合征和2型糖尿病的遗传基础可能是相关的，甚至是相同的。越来越清楚的是，炎症反应的成员在代谢综合征包括糖尿病和肥胖症的表型的病因学中是重要的。鉴于上述情况，我们将讨论炎症反应基因的遗传变异有助于PCOS病因学的假设。我们建议通过在一组PCOS病例和对照组中描述~30个炎症反应基因的变异来验证这一假设。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研究，其中我们检测了约43个候选基因内的单核苷酸多态性（SNP）与约1000名PCOS女性和约1000名BMI和种族匹配的对照女性之间的关联。SNP将覆盖每个基因的编码区和20 kb上游和下游，并将从HAPMAP项目中选择以获得最大信息量。在目标2中，将通过使用有希望的单倍型块的深度测序和进一步的关联研究来鉴定潜在的功能变体，更详细地分析有希望的基因/区域。目的3将检验在目的1 + 2中鉴定的基因的表达模式在PCOS中改变的假设。这些研究对于确定导致PCOS病因学的基因以及该综合征中受干扰的主要生物学途径至关重要。此外，患有PCOS的女性患T2DM的风险增加了7倍，使PCOS成为女性患T2DM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提供对T2DM遗传学和病因学的深入了解，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，其特征是男性性激素升高和月经不规律，并且还与肥胖、胰岛素抵抗和发生2型糖尿病（T2DM）的风险增加7倍有关。由于炎症反应在与PCOS相关的疾病中很重要，如代谢综合征，糖尿病和肥胖症，我们假设炎症反应途径中的基因也有助于PCOS，并建议测试约43个炎症反应基因在PCOS中的作用。这些研究对于确定导致PCOS病因的基因至关重要，PCOS是这种综合征中受到干扰的主要生物学途径，并且可能还提供了对T2DM（西方社会日益常见的疾病）的遗传学和病因学的见解。

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.