Genetic Epidemiology of Ovarian Aging

描述(申请人提供)：卵巢是一个独特的器官，因为与功能衰退(事实上，坦率地说是衰竭)相关的年龄似乎保持不变，尽管寿命越来越长。除了种群中这一明显的生物常数外，更年期发生的年龄以及卵母细胞数量和生殖能力的下降速度都存在广泛的个体间差异。我们提出了一项关于遗传和环境因素在生殖衰老中影响特定年龄变异性的研究。我们假设卵巢老化，如腔卵泡计数(AFC)所反映的，在很大程度上是由常见的遗传多态决定的，这些遗传多态影响初始卵母细胞捐赠和或随时间推移的卵母细胞损失率，从而降低任何给定年龄的腔卵泡计数。我们进一步假设AFC将是卵巢老化的一个更好的标志物。我们建议建立一个由1250名不同种族、定期骑自行车的女性组成的队列，年龄在25-45岁之间，她们将为DNA和其他生物标记物提供血液样本，接受经阴道超声检查以获得AFC，并完成问卷调查和人体测量。在具体目标1中，我们将通过将AFC与其他可用的生物标记物FSH、FSH/LH和抑制素B进行比较来表征AFC作为卵巢年龄的标志物，并确定这些关系的年龄修正效果。在特定的目标2中，我们将研究DAZL(在类无精子症中缺失)的遗传多态频率与相互作用的蛋白质和RNA基因以及有腔卵泡计数之间的关系。在具体目标3中，我们将确定种族/民族、体脂、主动和被动吸烟与AFC之间的独立于年龄的关联，并探索已识别的基因多态对这些关系的影响。在具体目标4中，我们将基于完成为期三年的跟踪检查的大约450名妇女，确定AFC随时间的变化及其与遗传和环境特征的关系。这个项目有几个独特的优势。这些包括：1)生殖内分泌学家、分子遗传学家和流行病学家的合作；2)广泛的基于人群的策略，将更充分地将AFC作为卵巢老化的预期标志；3)使用多民族人口来记录种族/民族差异；以及4)建立一个可以纵向跟踪的队列，将AFC的变化率与卵巢衰老的遗传风险因素联系起来。

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.