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性的过程，三体性是人类受孕中最常见的染色体异常，也是妊娠丢失和严重精神发育迟滞的主要原因。高龄产妇是唯一确定的风险因素。这个项目（a）测试这种关联是否反映了卵巢的加速老化，（B）检查与卵巢早衰相关的遗传特征的联系。我们推测，三体性的出现是卵母细胞池大小（卵巢年龄）的函数，在任何特定的年龄，卵母细胞池较小的妇女中，三体性风险增加。卵母细胞的数量在出生前是最高的，随着女性年龄的增长而减少。在任何一个特定的年龄段，妇女的死亡人数都各不相同。小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（丢失）加速所致。对这两个过程的原因知之甚少。较小的卵母细胞池的一个可能原因是FMR 1基因上CGG重复序列的大小，这与卵巢早衰有关。我们推测FMR 1重复序列的大小与三体相关。该应用程序利用已经收集的数据。对于卵母细胞池假说的检验，主要数据来自100例三体妊娠丢失（病例）和279例活产对照，以及两个妊娠丢失的辅助对照组。卵母细胞池大小的激素指标包括抗苗勒管激素、促卵泡激素和卵泡刺激素B。对于与FMR 1重复大小的关联的测试，样本包括206个三体病例和548个对照，以及两个附属的比较组。具体目标是：1.检测三体性病例中的激素水平是否比相同年龄的活产对照组中的激素水平指示更早的卵巢年龄，并评估相关性的特异性。2.检测三体病例中母体FMR 1重复序列长度是否比对照组长。3.通过研究FMR 1重复序列大小与激素指标的关系来阐明机制。这些假说的证实对研究三体形成的机制和为妇女提供怀孕咨询具有重要意义。这项申请旨在阐明导致三体性的过程，三体性是人类受孕中最常见的染色体异常，也是流产和严重智力迟钝的主要原因。它检验了与母亲年龄的强相关性反映了卵巢加速老化的假设。本研究对于希望延迟生育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.