Genetic Epidemiology of Ovarian Aging

描述（由申请人提供）：卵巢是一个独特的器官，尽管寿命增加，但与功能下降（事实上，坦率的失败）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，广泛的个体间差异存在于更年期发生的年龄和卵母细胞数量和生殖能力下降的速度。我们建议研究影响生殖衰老年龄特异性变异的遗传和环境因素。我们假设卵巢老化，正如由窦卵泡计数（AFC）所反映的那样，在很大程度上是由共同的遗传多态性决定的，这些遗传多态性会影响初始的卵母细胞禀赋和或随着时间的推移而导致的卵母细胞失失率，从而降低任何给定年龄的窦卵泡计数。我们进一步假设AFC将是卵巢衰老的改进标记。我们建议建立一个1250人的队列，年龄在25-45岁之间，种族多样，定期骑行的女性，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志物（FSH、FSH/LH和抑制素B）进行比较，将其描述为卵巢年龄的标志，并将确定年龄对这些关系的影响。在特异性目标2中，我们将研究DAZL（在无精子症样中缺失）遗传多态性频率、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，我们将确定独立于年龄的种族/民族、体脂、主动和被动吸烟与AFC之间的关系，并通过已识别的遗传多态性探索这些关系的影响修饰。在具体目标4中，我们将根据大约450名完成三年随访检查的妇女确定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。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)广泛的基于人群的策略，将更充分地表征AFC作为卵巢衰老的前瞻性标志物；3)使用多民族人群来记录种族/民族差异；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危险因素联系起来。

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.