Trisomy and ovarian age: An epidemiologic study

描述（由申请人提供）：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，也是导致妊娠失败和严重智力迟钝的主要原因。高龄产妇是唯一确定的风险因素。本项目(a)检验这种关联是否反映卵巢加速衰老，(b)检验与卵巢早衰相关的遗传特征之间的联系。我们假设三体是作为卵母细胞池大小（卵巢年龄）的函数出现的，在任何给定的年龄，卵母细胞池较小的女性患三体的风险增加。出生前卵母细胞的数量最多，随着女性年龄的增长而减少。在任何给定的年龄，这个数字都因女性而异。小池可能是由于胎儿发育过程中卵母细胞产生减少或卵母细胞闭锁（丢失）加速造成的。人们对这两个过程的原因知之甚少。卵母细胞池变小的一个可能原因是FMR1基因上的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。这个应用程序利用已经收集的数据。为了检验卵母细胞池假说，主要数据来自100例三体妊娠失败的妇女（病例）和279例活产的对照，以及两个妊娠失败的附属对照组。卵母细胞池大小的激素指标包括抗苗勒管激素、促卵泡激素和抑制素b。为了检测与FMR1重复序列大小的关系，样本包括206例三体病例和548例对照组，以及两个附属对照组。具体目标是：1。测试激素水平是否表明三体患者的卵巢年龄比相同年龄的活产对照组更早，并评估相关性的特异性。2. 检测三体病例中母体FMR1重复序列大小是否比对照组长。3. 通过检测FMR1重复序列大小与激素指标的关系来阐明其机制。这些假设的证实对三体形成机制的研究和对妇女怀孕咨询的潜在应用都有意义。本应用程序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，也是导致妊娠失败和严重智力迟钝的主要原因。它验证了与母亲年龄的强烈关联反映了卵巢加速衰老的假设。该项目对希望推迟生育到老年的妇女进行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.