Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Men and Children

通过定义与男性和儿童 PCOS 遗传风险因素相关的表型来剖析 PCOS 生理学

• 批准号: 10230375
• 负责人: Jia Zhu
• 金额: $ 7.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230375
• 关键词: Adrenal Glands; Affect; Androgens; Asthma; Biochemical; Bioinformatics; Biological; Birth; Boston; Caring; Child; Childhood; Classification; Clinical; Complex; Computational Biology; Counseling; Data; Denmark; Development; Diagnosis; Disease; Dyslipidemias; Endocrinology; Event; Fellowship; Fellowship Program; Female; First Degree Relative; Foundations; Functional disorder; Future; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Techniques; Genetic study; Goals; Gonadotropins; Grant; Health; Health Care Costs; Human Genetics; Hyperandrogenism; Individual; Institutes; Insulin Resistance; Lead; Learning; Longitudinal Studies; Male Pattern Baldness; Mentors; Mothers; Obesity; Ovarian; Parents; Pathogenesis; Pathway interactions; Pediatric Hospitals; Phenotype; Physiological; Physiology; Polycystic Ovary Syndrome; Production; Regulation; Reproduction; Reproductive Endocrinology; Research Personnel; Resources; Risk; Risk Factors; Testing; Training; Translational Research; Triad Acrylic Resin; Weight; Woman; aged; androgen biosynthesis; biobank; cardiometabolic risk; cardiometabolism; career; clinical care; clinical practice; cohort; folliculogenesis; genetic risk factor; genetic variant; genome wide association study; genomic data; girls; high body mass index; insight; insulin secretion; men; metabolic phenotype; ovarian dysfunction; phenome; phenotypic data; population based; premature adrenarche; prepuberty; reproductive; skills; targeted treatment

PROJECT SUMMARY/ ABSTRACT Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of all reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction and incurs an estimated $4.3 billion in annual U.S. healthcare costs. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Existing evidence suggests that PCOS is associated with both ovarian-related factors (gonadotropin secretion and action, folliculogenesis, androgen biosynthesis) and ovarian-independent factors (adrenal androgen biosynthesis, insulin secretion and action, weight and energy regulation), but which of these are the inciting events and which are the secondary consequences are unknown. The overall hypothesis for this study is that PCOS is not always primarily a disorder of female reproduction, but rather can be primarily a condition of hyperandrogenism and/or cardiometabolic dysregulation, with ovarian dysfunction as a secondary consequence. To test this hypothesis, this project will take advantage of a recent genome wide-association study (GWAS) that discovered numerous genetic variants that influence PCOS risk. Because these genetic variants are present in all individuals, this discovery provides a unique opportunity to study the phenotypic effects of genetic risk factors for PCOS in men and prepubertal children without the influence of ovarian factors. This project leverages the power of the UK Biobank, a population-based cohort of 176,367 unrelated men in the UK, and two longitudinal pediatric birth cohorts, the Copenhagen Studies on Asthma in Childhood (COPSAC) in Denmark with 558 children and the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK with 6,791 children. Genetic risk scores (i.e. estimated genetic susceptibility to PCOS) will be calculated in men from the UK Biobank and prepubertal children from COPSAC and ALSPAC and tested for associations with hyperandrogenic and cardiometabolic phenotypes. Characterizing the phenotypes in men and children who carry genetic risk factors for PCOS will provide a starting point for identifying specific biological pathways underlying the pathogenesis of PCOS, allow for the future development of targeted therapies for PCOS, and deepen our understanding of pediatric manifestations of genetic risk factors for PCOS. The fellowship training plan consists of a co-mentoring team composed of Dr. Joel Hirschhorn and Dr. Yee-Ming Chan at the Broad Institute and the Division of Endocrinology at Boston Children’s Hospital (BCH). Dr. Hirschhorn’s lab and the Broad Institute will provide Dr. Zhu with extensive training in human genetics of polygenic disease and computational biology and bioinformatics. Dr. Chan’s lab will provide Dr. Zhu with training in scientific and clinical pediatric reproductive endocrinology. The pediatric endocrinology fellowship program at BCH will provide Dr. Zhu with exceptional training in the clinical practice of pediatric endocrinology.

项目概要/摘要 多囊卵巢综合症 (PCOS) 是一个主要的健康问题，影响着多达 10% 的人 育龄妇女。这种复杂、异质的情况通常具有以下三个特征： 排卵功能障碍、雄激素过多症和心脏代谢功能障碍，预计造成 43 亿美元的损失 美国每年的医疗费用。尽管进行了广泛的生理学和遗传学研究，多囊卵巢综合症的治疗 仍然受到对该疾病病理生理学不完全理解的限制。现有证据 表明 PCOS 与卵巢相关因素（促性腺激素的分泌和作用、 卵泡发生、雄激素生物合成）和卵巢独立因素（肾上腺雄激素生物合成、 胰岛素分泌和作用、体重和能量调节），但其中哪些是诱发事件以及 哪些次要后果尚不清楚。本研究的总体假设是 PCOS 不是 始终主要是女性生殖疾病，但也可能主要是雄激素过多症的病症 和/或心脏代谢失调，继发性后果是卵巢功能障碍。为了测试这个 假设，该项目将利用最近的基因组广泛关联研究（GWAS），该研究 发现了许多影响多囊卵巢综合症风险的基因变异。因为这些基因变异存在于 对于所有个体来说，这一发现提供了一个独特的机会来研究遗传风险的表型效应 男性和青春期前儿童 PCOS 的因素，不受卵巢因素的影响。这个项目 利用英国生物银行的力量，这是一个由 176,367 名英国无亲属关系男性组成的人口队列，以及 两个纵向儿科出生队列，哥本哈根儿童哮喘研究 (COPSAC) 丹麦有 558 名儿童，英国雅芳家长和儿童纵向研究 (ALSPAC) 6,791 名儿童。将计算男性的遗传风险评分（即估计对 PCOS 的遗传易感性） 来自英国生物银行和来自 COPSAC 和 ASPAC 的青春期前儿童，并测试了与 高雄激素和心脏代谢表型。描述男性和儿童的表型特征 携带 PCOS 遗传风险因素将为识别特定的生物学途径提供起点 揭示 PCOS 发病机制的基础，为未来开发 PCOS 靶向治疗奠定基础 加深我们对 PCOS 遗传危险因素的儿科表现的了解。 该奖学金培训计划由 Joel Hirschhorn 博士和 Dr. Joel Hirschhorn 组成的共同指导团队组成。 布罗德研究所和波士顿儿童医院 (BCH) 内分泌科的陈怡明 (Yee-Ming Chan) 博士。 Hirschhorn 博士的实验室和布罗德研究所将为朱博士提供人类遗传学方面的广泛培训 多基因疾病和计算生物学和生物信息学。陈博士的实验室将为朱博士提供 科学和临床儿科生殖内分泌学培训。儿科内分泌学奖学金 BCH 项目将为朱博士提供儿科内分泌临床实践方面的特殊培训。