Increasing understanding of causes of stillbirth: Is the effect of maternal stress on stillbirth mediated by methylation of stress-related genes?

项目摘要/摘要 作为一个主要的全球公众，每年260万死产的负担使死产与新生儿死亡率平起平坐 健康问题。在美国，每1000名新生儿中有6.0人的死胎率一直超过婴儿死亡率 死亡率很高，高于其他25个高收入国家的死胎率。此外，还有很高的 种族不平等，黑人家庭面临的死胎率是白人的两倍多。已经有了 全球持续忽视预防死产，以及联合国每1000名新生儿中有12名死产的目标 到2030年，不太可能实现这一目标。美国疾病控制与预防中心关于死亡的重要统计报告不包括死产，只有疾病控制与预防中心 2014年开始报道死产原因。一个障碍是对原因的有限了解。范围广泛的 从冰岛的1.3到巴基斯坦的43.1的死胎率表明，大多数死产还不是不可避免的 三分之一的死产无法解释。最近一项对489,089名死产的审查发现，合并估计有32%的死产 高收入国家“不明原因”的死产--比不明原因婴儿的发生率高出近400倍 美国的死亡。对病因的有限了解减少了预防的机会。压力带来了希望 作为一个可能的原因，有流行病学证据表明与死产有关，但目前还没有研究 评估了生物学上的合理性。一种可能的机制是通过表观遗传沉默应激相关基因 DNA甲基化。使用嵌套病例对照设计，数据来自不同种族的人群， NICHD创建的死胎合作研究网络(SCRN)，这项研究将评估 母体应激对死产的影响是由应激相关基因甲基化介导的。研究的目标是 为了：(1)测试压力影响的模型(由社会经济地位、童年虐待和 重大生活事件)在SCRN人群中的死产(663例死产，1,439例活产)和一个66人亚组 非异常足月死产和132例活产；(2)使用因果调解分析评估证据 胎盘组织应激相关候选基因甲基化介导；(3)开展探索性研究 评估种族/族裔对这些影响的影响；以及(4)使用不可知论方法进一步评估 通过表观基因组范围的甲基化进行调节。通过证明生物学上的合理性，这项研究可以做出贡献 了解可预防的原因，强调压力在死胎率不平等中的作用，产生 新的假设，并通知制定个人和政策层面的干预措施，以减少 死产数字。提议的目标将直接促进NICHD改善怀孕的目标 结果和确定暴露以解释胎儿损失，以及优先处理的研究领域 死产的负担。拟议的培训计划将在哥伦比亚大学内实施，哥伦比亚大学是世界上 卓越的研究型大学，为申请者提供表观遗传学、生物信息学和高级 方法，将与优秀的赞助商团队，确保成功完成研究和 申请者转变为一名专注于死产预防的独立研究人员。

PROJECT SUMMARY/ABSTRACT The burden of 2.6 million stillbirths a year places stillbirth on a par with neonatal mortality as a major global public health issue. In the U.S., the stillbirth rate of 6.0 per 1000 total births has consistently exceeded the infant mortality rate, and is higher than the stillbirth rates of 25 other high-income countries. Moreover, there is high racial inequity, with Black families facing a stillbirth rate more than double that of whites. There has been persistent global inattention to stillbirth prevention, and the United Nations’ goal of 12 stillbirths per 1000 births by 2030 is unlikely to be met. The CDC’s vital statistics report on mortality excludes stillbirths, and the CDC only began reporting on causes of stillbirth in 2014. One barrier is limited knowledge on causes. The wide range of stillbirth rates, from 1.3 in Iceland to 43.1 in Pakistan, demonstrates that most stillbirths are not inevitable, yet one-third of stillbirths are unexplained. A recent review of 489,089 stillbirths found a pooled estimate of 32% of stillbirths “unexplained” in high-income countries—nearly 400 times higher than the rate of unexplained infant deaths in the U.S. Limited understanding of causes reduces opportunities for prevention. Stress holds promise as a possible cause, with epidemiological evidence of an association with stillbirth, but no studies have yet assessed biological plausibility. One potential mechanism is epigenetic silencing of stress-related genes through DNA methylation. Using a nested case-control design with data from a racially diverse population-based cohort, the NICHD-founded Stillbirth Collaborative Research Network (SCRN), this study will assess whether the effect of maternal stress on stillbirth is mediated by methylation of stress-related genes. Study aims are to: (1) test models for the effect of stress (as measured by socioeconomic status, childhood maltreatment, and significant life events) on stillbirth in the SCRN population (663 stillbirths, 1,439 live births) and a subgroup of 66 non-anomalous full-term stillbirths and 132 livebirths; (2) use causal mediation analysis to assess evidence for mediation by methylation of stress-related candidate genes in placental tissue; (3) carry out exploratory assessment of modification of these effects by race/ethnicity; and (4) use an agnostic approach to further assess mediation by epigenome-wide methylation. By demonstrating biological plausibility, the study could contribute to knowledge of preventable causes, highlight the role of stress in inequity in stillbirth rates, generate new hypotheses, and inform the development of interventions at individual and policy levels to reduce stillbirth numbers. The proposed aims will directly contribute to the NICHD’s goals of improving pregnancy outcomes and identifying exposures to explain fetal loss, as well as the high-priority research area of addressing the burden of stillbirth. The proposed training plan will be delivered within Columbia University, one of the world’s preeminent research universities, providing the applicant with skills in epigenetics, bioinformatics, and advanced methods that will, with an outstanding sponsor team, ensure successful completion of the study and the applicant’s transition to a career as an independent researcher focused on stillbirth prevention.