Impact of fertility status on epigenetic indicators of future health risk

生育状况对未来健康风险表观遗传指标的影响

基本信息

批准号：
10577544
负责人：
Anna Kaitlyn Knight
金额：
$ 23.48万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577544
关键词：
Acceleration Affect Age Area Biological Blood specimen Cardiovascular Diseases Cause of Death Chronic Disease Chronology Clinical Data Counseling DNA Methylation Development Diagnosis Disease Early Intervention Early identification Early treatment Environment Epigenetic Process Evaluation Exhibits Fertility Fertilization in Vitro Fibroid Tumor Future Gene Expression Gene Expression Regulation Goals Health Health Status Hormones Individual Infertility Inflammation Intervention Life Link Literature Menopause Metabolic Metabolic Diseases Metabolic syndrome Methylation Molecular Morbidity - disease rate Non-Insulin-Dependent Diabetes Mellitus Obesity Onset of illness Pathway interactions Pattern Physiological Processes Polycystic Ovary Syndrome Postmenopause Pregnancy loss Preimplantation Diagnosis Prevalence Prevention Preventive care Preventive measure Prospective cohort Recurrence Risk Risk Factors Services Site Stroke Time United States Woman Work adverse outcome biobank candidate identification cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor critical period diminished ovarian reserve disorder risk embryo cryopreservation endometriosis experience fertility preservation follow-up healthspan idiopathic infertility infertility treatment insight lifetime risk mortality mortality risk mullerian-inhibiting hormone oocyte cryopreservation ovarian dysfunction ovarian reserve personalized medicine predictive marker reproductive risk mitigation screening

项目摘要

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.

项目概要不孕不育症影响着美国大约 10% 的女性，而且这种情况正在变得越来越严重常见的。最近的研究表明，除了生殖后果外，不孕症还与慢性病和全因死亡率的发展。这种现象的两个例子是文献支持心血管疾病 (CVD) 和代谢综合征 (MetS) 的风险，这两种疾病这在女性中更为常见，并且绝经后风险更高。 CVD是导致女性死亡，MetS 的患病率约为 30%，并增加死亡风险。有可能不孕症与 CVD 和 MetS 之间存在共同的途径，例如炎症增加，可以调节这两种情况的风险。因此，评估不孕女性未来的 CVD 和 MetS 提供了在不孕不育的情况下采取预防措施和个性化治疗的独特机会评价。识别 CVD 和 MetS 风险增加的女性的一种方法是检查差异在DNA甲基化中。 DNA 甲基化是基因表达响应变化的一种机制环境、激素状态或其他生理过程。这些变化可能发生在症状性疾病的发作，并可以识别出不良结果风险增加的女性。这项研究将在 125 名女性中评估了三种基于 DNA 甲基化的长期健康、CVD 和 MetS 预测因子不孕症和 125 名没有不孕症但正在接受体外受精的女性。我们也会评估与卵巢储备功能低下有关，卵巢储备功能可预测绝经时间，也可能与风险增加。首先，我们将评估可预测健康寿命的细胞年龄加速指标和全因死亡率。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 MetS 甲基化风险评分。我们假设不孕症和卵巢储备功能低下会导致与年龄加速有关，这将作为未来疾病的一般标志死亡。我们假设 CVD 甲基化风险评分与不孕症和卵巢功能低下有关由于不孕不育与后来的 CVD 发展之间的假定联系而储备。最后，我们假设不孕症和卵巢储备功能低下与肥胖等 MetS 甲基化风险评分增加相关和其他 MetS 风险因素在不孕症中发挥着作用。如果成功，该提案将提供进一步的证据不孕症与其他长期健康状况有关，并且可以确定未来的预测标记可以作为不孕症治疗的一部分进行评估的疾病。该提案也将告知后续 R01 提交文件旨在进一步确定不孕不育的非生殖影响，并允许进行随访直至疾病发生发病。