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: 10395951
• 负责人: Jia Zhu
• 金额: $ 8.11万
• 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/10395951
• 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.

项目摘要/摘要 多囊卵巢综合征（PCOS）是主要的健康问题，最多影响所有人的10％ 生殖时代的妇女。这种复杂的，异质的状况通常以三合一为特征 排卵功能障碍，超雄激素和心脏代谢功能障碍，估计有43亿美元 在年度美国医疗保健费用中。尽管有广泛的生理和遗传研究，但PCOS的治疗 由于对该疾病的病理生理学的不完全理解而限制。现有证据 表明PCOS与卵巢相关因素（促性腺激素分泌和作用， 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， 胰岛素分泌和动作，体重和能量调节），但其中哪一个是煽动性事件和 这是次要后果未知。这项研究的总体假设是PCOS不是 总是主要的女性繁殖障碍，而是主要的症状。 和/或心脏代谢失调，卵巢功能障碍是次要后果。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），该研究是 发现了许多影响PCOS风险的遗传变异。因为这些遗传变异存在于 所有个人，这一发现提供了研究遗传风险的表型影响的独特机会 男性和青春期前儿童的PCOS因素，而没有卵巢因素的影响。这个项目 利用英国生物银行的力量，这是一个以人口为基础的人群 两个纵向小儿出生队列，哥本哈根关于儿童哮喘（COPSAC）的研究 丹麦有558名儿童和对英国父母和儿童（ALSPAC）的雅芳纵向研究 6,791个孩子。男性将计算遗传风险评分（即对PCOS的遗传敏感性） 来自英国的生物库和来自Copsac和Alspac的青春期前儿童，并测试了与 超雄激素和心脏代谢表型。表征男性和儿童的表型 携带PCOS的遗传危险因素将为识别特定生物学途径提供一个起点 PCOS的发病机理的基础，允许对PCOS的靶向疗法的未来开发，以及 加深我们对PCOS遗传危险因素的小儿表现的理解。 奖学金培训计划由一个由乔尔·赫希霍恩（Joel Hirschhorn）和博士（Dr.）组成的联盟团队组成。 Broad Institute的Yee-Ming Chan和波士顿儿童医院（BCH）的内分泌学系。 Hirschhorn博士的实验室和Broad Institute将为Zhu博士提供有关人类遗传学的广泛培训 多基因疾病与计算生物学和生物信息学。 Chan博士的实验室将为朱博士提供 科学和临床小儿生殖内分泌学的培训。小儿内分泌学奖学金 BCH的计划将为朱博士提供针对小儿内分泌学临床实践的特殊培训。