Genetic Epidemiology of Ovarian Aging

卵巢衰老的遗传流行病学

• 批准号: 7073460
• 负责人: MARCELLE Ivonne CEDARS
• 金额: $ 142.77万
• 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/7073460
• 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）：卵巢是一种独特的器官，尽管寿命不断增加，但与功能衰退（实际上是明显的衰竭）相关的年龄似乎保持不变。除了人口中这种明显的生物学常数之外，绝经发生的年龄以及卵母细胞数量和生殖能力的下降速度都存在广泛的个体差异。我们建议对影响生殖衰老的年龄特异性变异性的遗传和环境因素进行研究。我们假设，窦卵泡计数（AFC）所反映的卵巢衰老很大程度上是由常见的遗传多态性决定的，这些遗传多态性会影响初始卵母细胞的禀赋和/或随着时间的推移卵母细胞的丢失率，从而降低任何给定年龄的窦卵泡计数。我们进一步假设 AFC 将成为卵巢衰老的改进标志。我们建议建立一个由 1250 名年龄在 25-45 岁、不同种族、经常骑自行车的女性组成的队列，她们将提供 DNA 和其他生物标志物的血液样本，接受经阴道超声检查以获得 AFC，并完成问卷和人体测量。在具体目标 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 描述为卵巢年龄的标志物，并确定这些关系随年龄的影响。在具体目标 2 中，我们将检查 DAZL（无精子症样缺失）中遗传多态性的频率、相互作用的蛋白质和 RNA 基因以及窦卵泡计数之间的关系。在具体目标 3 中，我们将独立于年龄确定种族/民族、身体脂肪、主动和被动吸烟与 AFC 之间的关联，并探索通过识别的遗传多态性对这些关系的影响修改。在具体目标 4 中，我们将基于完成三年随访检查的约 450 名女性，确定 AFC 随着时间的变化及其与遗传和环境特征的关系。该项目有几个独特的优势。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) 一项基于广泛人群的策略，该策略将更全面地将 AFC 描述为卵巢衰老的前瞻性标志物； 3）使用多种族人群来记录种族/民族差异，4）建立可纵向跟踪的队列的能力，将 AFC 的变化率与卵巢衰老的遗传风险因素联系起来。