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: 8310181
• 负责人: Margrit Urbanek
• 金额: $ 55.68万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310181
• 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 Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Gonadal Steroid Hormones; Haplotypes; Health; 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; Phenotype; Polycystic Ovary Syndrome; Population; Process; RNA; Recruitment Activity; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Skin; Societies; Staging; Susceptibility Gene; Syndrome; System; TNF gene; Testing; Time; Variant; Visceral; Woman; base; case control; cohort; follow-up; insight; insulin sensitivity; liver biopsy; male; member; reproductive; subcutaneous; young woman

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.

描述（由申请人提供）：多囊卵巢综合征（PCOS）是最常见的年轻女性内分泌疾病，影响西方社会的生殖年龄妇女约7％。它的特征是高雄激素血症和月经不规则。除了这些生殖表型外，PCOS还与肥胖，胰岛素抵抗和增加2型糖尿病（T2DM）的风险增加有关。 PCOS是可遗传的，并且具有许多与胰岛素抵抗，糖尿病和肥胖症共同的特征，这表明PCOS和T2DM的遗传基础可能相关甚至相同。越来越清楚的是，炎症反应的成员在包括糖尿病和肥胖症在内的代谢综合征的表型的病因中很重要。鉴于以上，我们将解决以下假设：炎症反应基因的遗传变异有助于PCOS的病因。我们建议通过表征〜30个炎症反应基因的变异来检验这一假设，其中PCOS病例和对照组中的差异。我们的分析将分为三个具体目标。最初的分析将包括一项关联研究，在该研究中，我们测试了〜43个候选基因中的单核苷酸多态性（SNP）和〜1000名PCOS女性和〜1000 BMI和种族匹配的对照女性之间的关联。 SNP将涵盖每个基因的编码区域和20 kb的上游和下游，并将从HAPMAP项目中选择以获得最大的信息性。在AIM 2中，将通过使用有希望的单倍型块和进一步关联研究的深层测序来鉴定潜在的功能变体，从而更详细地分析有希望的基因/区域。 AIM 3将检验以下假设：在PCOS中，AIM 1 + 2中鉴定的基因的表达模式发生了变化。这些研究对于鉴定有助于PCOS病因的基因和综合征干扰的主要生物学途径至关重要。此外，患有PCOS的女性患T2DM的风险增加了七倍，使PCOS可能是女性发展T2DM的主要危险因素。因此，阐明这些基因在PCOS病因中的作用也应提供对可以在其他人群中进行测试的T2DM遗传学和病因的见解。 公共卫生相关性：多囊卵巢综合征（PCOS）是常见的内分泌疾病，其特征是男性性激素升高和月经不规则性，也与肥胖，胰岛素抵抗，7倍增加了患2型2型糖尿病型糖尿病（T2DM）的风险。由于炎症反应在与代谢综合征，糖尿病和肥胖症等PCOS相关的疾病中很重要，因此我们假设炎症反应途径中的基因也有助于PCOS，并提出测试〜43个炎症反应基因在PCOS中的作用。这些研究对于鉴定有助于PCOS病因的基因至关重要，PCOS是该综合征中受干扰的主要生物学途径，并且也有可能深入了解T2DM的遗传学和病因学，T2DM是西方社会中日益常见的疾病。