Genetic Epidemiology of Ovarian Aging

卵巢衰老的遗传流行病学

• 批准号: 6870646
• 负责人: MARCELLE Ivonne CEDARS
• 金额: $ 121.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-06 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870646
• 关键词: African American; Alaskan Native American; Asians; Hispanic Americans; Native Americans; Pacific Islander; adipose tissue; adult human (21+); aging; blood chemistry; caucasian American; clinical research; egg /ovum; fluorescence polarization; gene environment interaction; genetic polymorphism; human subject; longitudinal human study; menopause; oogenesis; polymerase chain reaction; questionnaires; racial /ethnic difference; tobacco abuse; ultrasonography; women' s health

DESCRIPTION (provided by applicant): The ovary is a unique organ in that the age associated with decline in function (in fact, frank failure) appears to have remained constant despite increasing longevity. Beyond this apparent biological constant in the population, wide interindividual variability exists both in the age at which menopause occurs and the rate of decline in oocyte number and reproductive capability. We propose a study of the genetic and environmental factors that influence the age-specific variability in reproductive aging. We hypothesize ovarian aging, as reflected by antral follicle count (AFC), is largely determined by common genetic polymorphisms that impact the initial oocyte endowment and or the rate of oocyte loss over time thus lowering antral follicle count for any given age. We further hypothesize AFC will be an improved marker of ovarian aging. We propose to develop a cohort of 1250, ethnically diverse, regularly cycling women, ages 25-45 who will provide blood specimens for DNA and other biomarkers, undergo a transvaginal ultrasound to obtain AFC, and complete questionnaires and anthropometric measurements. In Specific Aim 1, we will characterize AFC as a marker of ovarian age by comparing it to other available biomarkers, FSH, FSH/LH, and inhibin B, and will determine effect modification of these relations by age. In Specific Aim 2, we will examine the relationship between the frequency of genetic polymorphisms in DAZL (Deleted in Azoospermia-Like), and interacting protein and RNA genes, and antral follicle count. In Specific Aim 3, we will determine the association between race/ethnicity, body fat, and active and passive smoking and AFC independently of age, and explore the effect modification of those relationships by identified genetic polymorphisms. In Specific Aim 4, we will determine the change in AFC over time and its relation to genetic and environmental characteristics based on approximately 450 women who complete the three-year follow-up examination. This project has several unique strengths. These include: 1) the collaboration of a reproductive endocrinologist, a molecular geneticist and an epidemiologist; 2) a broad population based strategy which will more fully characterize AFC as a prospective marker of ovarian aging; 3) the use of a multi-ethnic population to document racial/ethnic differences and 4) the ability to establish a cohort that can be followed longitudinally to associate rate of change in AFC with genetic risk factors for ovarian aging.

描述（由申请人提供）：卵巢是一个独特的器官，因为与功能下降相关的年龄（实际上，Frank失败）似乎仍然保持恒定，尽管寿命增加了。除了人群中这种明显的生物学常数外，更年期发生的年龄以及卵母细胞数量和生殖能力的下降率都存在广泛的个体差异。我们建议对影响生殖衰老特异性变异性的遗传和环境因素的研究。我们假设卵巢卵泡计数（AFC）反映出卵巢衰老，在很大程度上取决于影响初始卵母细胞赋值的常见遗传多态性或或或或卵母细胞随时间降低的卵母细胞损失速率，从而降低了任何给定年龄的肛门卵泡数。我们进一步假设AFC将是卵巢衰老的改进标志。我们建议开发1250个种族多样的，定期自行车的妇女的队列，年龄在25-45岁之间，她们将为DNA和其他生物标志物提供血液标本，经过经阴道超声以获得AFC，并进行完整的调查表和人源测量。在特定的目标1中，我们将通过将AFC与其他可用的生物标志物，FSH，FSH/LH和抑制素B进行比较，将AFC描述为卵巢时代的标记，并将确定按年龄对这些关系的效果修改。在特定的目标2中，我们将研究DAZL中遗传多态性的频率（在azoospermia样中删除），相互作用的蛋白质和RNA基因与肛门卵泡数之间的关系。在特定的目标3中，我们将独立于年龄独立于种族/种族，身体脂肪与活跃和被动吸烟与AFC之间的关联，并通过确定的遗传多态性探索这些关系的效果修饰。在特定的目标4中，我们将根据大约450名完成三年随访检查的女性，确定AFC随时间的变化及其与遗传和环境特征的关系。该项目具有多种独特的优势。其中包括：1）生殖内分泌学家，分子遗传学家和流行病学家的合作； 2）一种基于人口的广泛战略，将更充分地将AFC描述为卵巢衰老的前瞻性标志； 3）使用多民族人口记录种族/族裔差异，4）建立可以纵向遵循的队列的能力，以使AFC的变化率与卵巢衰老的遗传危险因素关联。