The Inflammatory Response Pathway in the Etiology of Polycystic Ovary Syndrome

多囊卵巢综合征病因中的炎症反应途径

• 批准号: 7897913
• 负责人: Margrit Urbanek
• 金额: $ 49.29万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897913
• 关键词: Address; Affect; Age; Biological; Biopsy; Candidate Disease Gene; Chromosome Mapping; Code; Custom; Diabetes Mellitus; Disease; Endocrine System Diseases; Ethnic Origin; Etiology; European; Exons; Fatty acid glycerol esters; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Gonadal Steroid Hormones; Haplotypes; IL8 gene; Individual; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Insulin Resistance; Introns; Irregular Menstruation; Knowledge; Light; Messenger RNA; Metabolic syndrome; Molecular Profiling; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Obesity; Pathway interactions; Pattern; Phenotype; Polycystic Ovary Syndrome; Population; Process; RNA; Recruitment Activity; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Skin; Societies; Staging; Susceptibility Gene; Syndrome; System; Testing; Time; Variant; Visceral; Woman; base; case control; cohort; follow-up; insight; insulin sensitivity; liver biopsy; male; member; public health relevance; reproductive; subcutaneous

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.

简介（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，影响了西方社会约7%的育龄妇女。它的特点是高雄激素血症和月经不规律。除了这些生殖表型外，多囊卵巢综合征还与肥胖、胰岛素抵抗和患2型糖尿病（T2DM）的风险增加有关。多囊卵巢综合征具有遗传性，与胰岛素抵抗、糖尿病和肥胖有许多共同特征，提示多囊卵巢综合征和2型糖尿病的遗传基础可能相关甚至相同。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）表型的病因学中是重要的。综上所述，我们将讨论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设。我们建议通过在PCOS患者和对照组中表征约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，在该研究中，我们将测试约43个候选基因中的单核苷酸多态性（snp）与约1000名PCOS患者和约1000名BMI和种族匹配的对照女性之间的关联。这些snp将覆盖每个基因的编码区和上下游20kb，并将从HAPMAP项目中选择，以获得最大的信息量。在Aim 2中，有希望的基因/区域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识别潜在的功能变体，从而更详细地分析。Aims 3将验证Aims 1 + 2中鉴定的基因表达模式在PCOS中发生改变的假设。这些研究对于确定导致多囊卵巢综合征病因的基因和该综合征中受干扰的主要生物学途径至关重要。此外，患有多囊卵巢综合征的女性发生2型糖尿病的风险增加了7倍，使多囊卵巢综合征成为女性发生2型糖尿病的主要危险因素。因此，阐明这些基因在多囊卵巢综合征病因学中的作用，也应该有助于了解T2DM的遗传学和病因学，从而在其他人群中进行检测。公共卫生相关性：多囊卵巢综合征（PCOS）是一种常见的内分泌紊乱，以男性性激素升高和月经不规律为特征，还与肥胖、胰岛素抵抗和2型糖尿病（T2DM）发病风险增加7倍有关。由于炎症反应在代谢综合征、糖尿病、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的发生，并提出检测约43种炎症反应基因在PCOS中的作用。这些研究对于确定多囊卵巢综合征（PCOS）病因的基因至关重要，该综合征的主要生物学途径受到干扰，并可能为T2DM（西方社会日益常见的疾病）的遗传学和病因提供见解。