Oxytocin sensitivity and postpartum hemorrhage: testing genetic and epigenetic biomarkers for improving maternal morbidity

项目摘要 产后出血是一种分娩并发症，在美国影响3-8%的分娩， 这意味着每年至少有120 000名新生儿。产后出血也是孕产妇死亡的主要原因。 全世界的死亡率。严重产后出血和需要侵入性治疗的出血的发生率，或 输血的人数在增加，特别是对引产的孕妇。严重出血也较多 在有色人种妇女中很常见，这导致了孕产妇健康的差异。催产素是一种天然存在的 激素以及用于刺激分娩、预防或治疗产后出血药物。催产素 结合子宫肌肉中可用的催产素受体，刺激收缩。虽然催产素是第一道防线 出血治疗，在分娩过程中给予催产素刺激宫缩的人更多 可能对产后施用的催产素的子宫收缩反应不太有效，导致 更多的出血和需要其他医疗或程序。目前，10人中有4人 尽管目前的临床预测工具没有将其确定为高风险，但仍然如此。这 不准确性和出血率的上升表明需要更多的研究来帮助确定可能的 这种潜在的危及生命的并发症的风险。因为那些无效的劳动合同或 个人/家族史（出血）更容易有产后出血，先天的作用 催产素功能/敏感性是本研究的主要焦点。因此，我们的实验室一直在研究 生物标志物可以通过测试遗传和表观遗传变异如何帮助识别有出血风险的人 催产素受体基因的突变与催产素反应和出血有关。在本提案中，我们使用 生物社会框架，以测试中心假设，即母体的催产素受体基因的变异， 可用于预测药理学催产素需求和出血。首先，我们将研究DNA甲基化 （表观遗传差异）从血液样本使用库存数据以及前瞻性收集的非侵入性 唾液样本与分娩和产后出血中催产素的需求相关。社会决定因素 将检查与DNA甲基化差异相关的健康状况;评估不良反应的作用。 环境在形成催产素受体表型中的作用。此外，我们还将测试DNA甲基化 影响子宫组织中的基因表达和催产素受体的可用性。第二，我们将研究 催产素受体基因的遗传变异与上述临床终点相关 通过测量子宫肌肉样本的收缩性来测试药理学反应。给定 临床医生没有办法预测催产素在产后紧急情况下的效果 出血，我们的目标是开发一种临床上有用的生物标志物测量内在催产素敏感性之前， 分娩或分娩。该项目的长期目标是使用生物标志物数据来改善临床决策- 制定、测试个性化干预措施和降低孕产妇发病率。

Project Summary Postpartum hemorrhage is a complication of childbirth that affects 3-8% of births in the United States, each year this represents a minimum of 120,000 births. Postpartum hemorrhage is also a primary cause of maternal mortality worldwide. Rates of severe postpartum hemorrhage and hemorrhage requiring invasive treatments or blood transfusions are on the rise, particularly for labors that are induced. Severe hemorrhage is also more common among women of color, contributing to disparities in maternal health. Oxytocin is a naturally occurring hormone as well as a medication used to stimulate labor, prevent or treat postpartum hemorrhage. Oxytocin binds available oxytocin receptors in uterine muscle, stimulating contraction. While oxytocin is the first-line hemorrhage treatment, people who have been given oxytocin to stimulate contractions during labor are more likely to have a less effective uterine contraction response to oxytocin administered postpartum, leading to more bleeding and the need for other medical treatments or procedures. Currently, 4 of 10 people who hemorrhaged, did so despite not having been identified as high risk by current clinical prediction tools. This inaccuracy and the rising rates of hemorrhage indicate that more research is needed to help identify possible risks for this potentially life-threatening complication. Because people with ineffective labor contractions or a personal/family history (of hemorrhage) are more likely to have postpartum hemorrhage, the role of innate oxytocin function/ sensitivity is the primary focus of this investigation. As such, our lab has been researching biomarkers that can help identify people at risk for hemorrhage by testing how genetic and epigenetic variation of the oxytocin receptor gene is associated with oxytocin response and hemorrhage. In this proposal, we use a biosocial framework to test the central hypothesis that maternal variation in the oxytocin receptor gene can be useful for predicting pharmacologic oxytocin needs and hemorrhage. First, we will examine DNA methylation (epigenetic differences) from blood samples using banked data as well as prospectively collected non-invasive salivary samples in association with oxytocin needs in labor and postpartum hemorrhage. Social determinants of health will be examined in association with DNA methylation differences; evaluating the role of adverse environments in shaping the oxytocin receptor epigenotype. Furthermore, we will test how DNA methylation affects gene expression and the oxytocin receptor availability in uterine tissues. Second, we will examine genetic variants of the oxytocin receptor gene in association with the clinical endpoints with the aforementioned specimens and test pharmacologic response by measuring contractility of uterine muscle specimens. Given that clinicians have no method of predicting how well oxytocin will work in the emergency of postpartum hemorrhage, we aim to develop a clinically useful biomarker measuring intrinsic oxytocin sensitivity before labor or birth occurs. The long-range goal of this project is to use biomarker data to improve clinical decision- making, test personalized interventions and lower maternal morbidity.