Impact of fertility status on epigenetic indicators of future health risk

项目总结 在美国，大约10%的女性受到不孕症的影响，而且越来越多的女性患有不孕症 很普通。最近的研究表明，除了生育后果，不孕不育还与 慢性病和全因死亡的发展。这一现象的两个例子是 文献支持的是心血管疾病(CVD)和代谢综合征(METS)的风险，两者都是 这在女性中更常见，绝经后风险增加。心脑血管疾病是导致 女性死亡，甲型肝炎的患病率约为30%，增加了死亡风险。很有可能 不孕不育与心血管疾病和蛋氨酸肾病之间存在共同的途径，例如炎症增加，这 可能会调节两种情况下的风险。因此，为未来的CVD和METS评估患有不孕症的妇女提供了 在不孕不育的背景下采取预防措施和个性化治疗的独特机会 评估。确定患心血管疾病和甲型肝炎风险增加的女性的一种方法是通过检查差异 在DNA甲基化方面。DNA甲基化是基因表达对变化做出反应的一种机制 在环境、荷尔蒙状态或其他生理过程中。这些变化可能发生在 出现症状性疾病，并可识别有不良后果风险增加的妇女。这项研究将 对125名女性进行基于DNA甲基化的三项长期健康、心血管疾病和蛋氨酸水平预测指标的评估 不孕症和125名非不孕症妇女正在接受体外受精。我们还将评估 与卵巢储备不足的关系，这是绝经时间的预测，也可能与 风险增加。首先，我们将评估一个预测健康跨度的细胞老化加速指标。 以及各种原因造成的死亡。然后，我们将利用CpG位点的组合来预测CVD甲基化风险 评分和单独的蛋氨酸甲基化风险评分。我们假设不孕不育和卵巢储备不足 与年龄加速有关，这将成为未来疾病和 死亡率。我们假设心血管疾病甲基化风险评分与不孕症和卵巢功能低下有关。 保留是因为不孕不育和后来的心血管疾病之间可能存在联系。最后，我们假设 不孕症和卵巢储备不足将与蛋氨酸甲基化风险分数增加有关，如肥胖 而其他蛋氨酸代谢综合征的风险因素在不孕不育中也起到了作用。如果成功，这项提议将提供进一步的证据 不孕不育与其他长期健康状况有关，并将确定未来的预测标志 可以作为不孕不育治疗的一部分进行评估的疾病。该提案还将通知后续 R01意见书，以进一步确定不孕不育的非生殖影响，并允许对疾病进行跟踪 开始了。

PROJECT SUMMARY Infertility affects approximately 10% of women in the United States and is increasingly becoming more common. Recent studies suggest that, in addition to its reproductive consequences, infertility is associated with the development of chronic disease and all-cause mortality. Two examples of this phenomenon that are supported by the literature are risks of cardiovascular disease (CVD) and metabolic syndrome (MetS), both of which are more common in women and have elevated risks after menopause. CVD is the leading cause of death in women, and MetS has a prevalence of approximately 30% and increases risk for mortality. It is likely that there are shared pathways between infertility and CVD and MetS, such as increased inflammation, which may modulate risk for both conditions. Thus evaluating women with infertility for future CVD and MetS provides a unique opportunity for preventative measures and personalized treatments within the context of infertility evaluations. One way to identify women at increased risk for CVD and MetS is through examining differences in DNA methylation. DNA methylation is one mechanism through which gene expression responds to changes in the environment, hormone status, or other physiologic processes. These changes may occur prior to the onset of symptomatic disease and can identify women at increased risk for adverse outcomes. This study will evaluate three DNA methylation-based predictors of long-term health, CVD, and MetS in 125 women with infertility and 125 women without infertility who are undergoing in vitro fertilization. We will also evaluate associations with low ovarian reserve, which is predictive of time to menopause and may also associate with increased risk. First, we will assess an indicator of cellular age acceleration that is predictive of health-span and all-cause mortality. Then, we will leverage combinations of CpG sites to predict a CVD methylation risk score and a separate MetS methylation risk score. We hypothesize that infertility and low ovarian reserve will be associated with increased age acceleration, which would serve as a general marker of future disease and mortality. We hypothesize that the CVD methylation risk score will be associated with infertility and low ovarian reserve due to putative links between infertility and later development of CVD. Finally, we hypothesize that infertility and low ovarian reserve will be associated with increased MetS methylation risk scores as obesity and other MetS risk factors play a role in infertility. If successful, this proposal would provide further evidence that infertility is linked to other long-term health conditions, and would identify a predictive marker of future disease that could be evaluated as part of treatment for infertility. This proposal will also inform subsequent R01 submissions to further establish non-reproductive impacts of infertility and allow for follow-up until disease onset.