Trisomy and ovarian age: An epidemiologic study

描述(申请人提供)：长期目标是阐明导致三体的过程，三体是人类受孕中最常见的染色体异常，也是导致妊娠丢失和严重智力低下的主要原因。产妇年龄的增加是唯一确定的风险因素。该项目(A)测试这种关联是否反映了卵巢的加速老化，以及(B)检查与卵巢早衰相关的遗传特征之间的联系。我们假设三体是卵细胞池大小(卵巢年龄)的函数，在任何给定的年龄，卵池较小的女性发生三体的风险都会增加。卵母细胞的数量在出生前最高，随着女性年龄的增长而减少。在任何给定的年龄段，这一数字因女性而异。小的卵池可能是由于胎儿发育过程中卵母细胞产量减少或卵母细胞闭锁加速(丢失)所致。人们对这两个过程的原因知之甚少。卵细胞池较小的一个可能原因是FMR1基因上CGG重复序列的大小，这与卵巢早衰有关。我们假设FMR1重复大小与三体有关。此应用程序利用已收集的数据。对于卵母细胞池假说的测试，主要数据来自100名三体妊娠丢失妇女(病例)和279名活产对照妇女，以及两组怀孕丢失的附属对照组。卵母细胞池大小的激素指标包括抗米勒激素、卵泡刺激素和抑制素B。为了测试与FMR1重复大小的相关性，样本包括206个三体病例和548个对照，以及两个附属的对照组。研究的具体目标是：1.检验三体病例中的激素水平是否表明卵巢年龄比相同年龄的活体对照中的卵巢年龄更高，并评估两者之间的相关性。2.检测三体病例母体FMR1重复长度是否长于对照组。3.通过检测FMR1重复大小与激素指标的关系，阐明FMR1重复大小与激素变化的关系。这些假说的证实对三体形成机制的研究和对女性怀孕咨询的潜在应用都具有重要意义。这项申请旨在阐明导致三体的过程，三体是人类受孕中最常见的染色体异常，也是导致妊娠丢失和严重智力低下的主要原因。它验证了一种假设，即与母亲年龄的强烈关联反映了卵巢的加速衰老。该项目对希望推迟生育年龄的妇女的咨询具有重要的临床意义。

DESCRIPTION (provided by applicant): The long-term goal is to elucidate the processes leading to trisomy, the most frequent chromosomal anomaly among human conceptions and a major cause of pregnancy loss and severe mental retardation. Advancing maternal age is the only established risk factor. This project (a) tests whether the association reflects accelerated aging in the ovary and (b) examines connections with a genetic characteristic associated with premature ovarian aging. We hypothesize that trisomy arises as a function of the size of the oocyte pool (ovarian age), with trisomy risk increased among women with smaller pools at any given chronologic age. The number of oocytes is highest before birth and decreases as women age. At any given chronologic age, the number varies from woman to woman. Small pools may result from diminished production of oocytes during fetal development or accelerated oocyte atresia (loss). Little is known about the causes of either process. One possible cause of a smaller oocyte pool is the size of the CGG repeat on the FMR1 gene, which has been associated with premature ovarian failure. We hypothesize that FMR1 repeat size is associated with trisomy. This application draws on already collected data. For tests of the oocyte pool hypothesis, the primary data derive from 100 women with trisomic pregnancy losses (cases) and 279 controls with live births, as well as two subsidiary comparison groups with pregnancy losses. Hormonal indicators of the size of the oocyte pool include anti- Mullerian hormone, follicle stimulating hormone and inhibin B. For tests of associations with FMR1 repeat size, the sample comprises 206 trisomy cases and 548 controls, as well as two subsidiary comparison groups. The specific aims are: 1. To test whether hormone levels indicate more advanced ovarian age among trisomy cases than among live birth controls of the same chronologic age and to assess the specificity of associations. 2. To test whether maternal FMR1 repeat size is longer in trisomy cases than in controls. 3. To elucidate mechanisms by examining the relation of FMR1 repeat size to hormonal indicators. Confirmation of the hypotheses has implications both for research on mechanisms of trisomy formation and potential application for counseling women about pregnancy. This application seeks to elucidate the processes leading to trisomy, the most frequent chromosomal anomaly among human conceptions and a major cause of pregnancy loss and severe mental retardation. It tests the hypothesis that the strong association with maternal age reflects accelerated aging in the ovary. This project has important clinical implications for counseling women who wish to delay childbearing to older ages.