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。除了这一明显的生物学常数在人口中，广泛的个体间差异存在于绝经发生的年龄和卵母细胞数量和生殖能力的下降速度。我们提出了一个研究的遗传和环境因素，影响生殖老化的年龄特异性变异。我们假设卵巢老化，反映了窦卵泡计数（AFC），在很大程度上是由常见的遗传多态性，影响初始卵母细胞禀赋和/或卵母细胞的损失率随着时间的推移，从而降低窦卵泡计数为任何给定的年龄。我们进一步假设AFC将是卵巢老化的一个改进的标志物。我们建议建立一个由1250名年龄在25-45岁、种族多样、经常骑自行车的女性组成的队列，她们将提供血液样本进行DNA和其他生物标志物检测，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和卵泡刺激素B进行比较来表征AFC作为卵巢年龄的标志物，并将确定这些关系随年龄的影响。在具体目标2中，我们将研究DAZL（无精子症样精子）基因多态性频率、相互作用蛋白和RNA基因与窦卵泡计数之间的关系。在具体目标3中，我们将确定人种/种族、体脂、主动吸烟和被动吸烟与AFC之间的相关性（与年龄无关），并通过确定的遗传多态性探索这些关系的效应修饰。在具体目标4中，我们将根据完成三年随访检查的约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。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）基于广泛人群的策略，其将更充分地表征AFC作为卵巢老化的前瞻性标志物; 3）使用多民族人口来记录种族/民族差异，以及4）能够建立一个队列，可以纵向跟踪AFC的变化率与卵巢衰老的遗传危险因素。

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.