Vitamin D: a link to racial disparities in birth outcomes

这项提案将解决我们对早产中难以解决的种族差异的理解上的差距， 先兆子痫通过探索这些途径的新机制。我们专注于母体维生素D，a 以前未探索的候选人对妊娠结局的影响。我们已经证明，维生素D缺乏是 在整个怀孕期间在黑人妇女中普遍存在，在白色妇女中明显不常见。 此外，新的数据表明，维生素D对炎症和其他已知的疾病有直接和间接的影响。 自发性早产（sPTB）和先兆子痫发病机制中的分子途径。因此，我们认为， 维生素D状态是sPTB和先兆子痫的一个未探索的危险因素。这个生殖的目标 流行病学研究旨在阐明母体维生素D状况、炎症和 参与维生素D代谢的基因多态性对sPTB和先兆子痫风险的影响。我们将 在两个种族和地理上多样化的多中心美国前瞻性研究中进行互补分析 队列：围产期合作项目（n= 55，908; 46%白色; 47%黑人）和NICHD母胎 医学单位网络高风险阿司匹林研究（n=917例妊娠; 33%白色，57%黑人）。首先，我们的目标是 确定母体维生素D状态与sPTB风险之间的独立关联， 先兆子痫，并确定在何种程度上这种关联是由母系种族修改。维生素D状况 使用血清25-羟基维生素D评估妊娠d26周。第二，我们将评估 母体维生素D状态对母体炎症的独立影响，并确定这种影响的程度 相关性被母系种族所改变。母体炎症将使用高敏C- 在妊娠d26周测量反应蛋白（CRP）。最后，我们将确定产妇和 胎儿/新生儿关键维生素D代谢位点的遗传变异对母体维生素D状况的影响，以及对 sPTB和先兆子痫。我们将研究其蛋白质产物直接参与代谢的基因， 维生素D：25-羟化酶（CYP 27 A1）、1a-羟化酶（CYP 27 B1）、维生素D结合蛋白（GC）、24- 羟化酶（CYP 24 A1）、维生素D受体（VDR）和视黄酸受体α（RARA）。这个项目是 高度响应NIH路线图倡议，考虑到流行病学专业知识的融合， 临床和生物科学。此外，该项目意义重大，因为产妇维生素D状况 可修改.改善维生素D状况的干预措施，如适度增加阳光照射， 维生素D补充剂，是廉价，安全和妇女可以接受的。鉴于高比例的 黑人妇女维生素D不足，以及sPTB和先兆子痫对 由于围产期发病率高，该项目具有极大的造福公众健康的能力。该提案旨在探讨妊娠期间母体维生素D状况作为以下风险因素的作用： 自发性早产和先兆子痫，这两种不良妊娠结局与 围产期发病率很高。研究假设预测，维生素D缺乏导致种族 自发性早产和先兆子痫的差异。改善孕妇的维生素D状况可能 是一个简单的战略，以减少黑人妇女的不良生育结果的过度情况下， 美国的

This proposal will address gaps in our understanding of the intractable racial disparities in preterm birth and preeclampsia by exploring novel mechanisms underlying these pathways. We focus on maternal vitamin D, a previously unexplored candidate influence on pregnancy outcome. We have shown that vitamin D deficiency is pervasive among black women throughout pregnancy and is significantly less common among white women. Further, new data indicate that vitamin D has direct and indirect influences on inflammation and other known molecular pathways in the pathogenesis of spontaneous preterm birth (sPTB) and preeclampsia. Therefore, vitamin D status is an unexplored risk factor for sPTB and preeclampsia. The goal of this reproductive epidemiologic study is to elucidate the interplay between maternal vitamin D status, inflammation, and polymorphisms in genes involved in vitamin D metabolism on the risk of sPTB and preeclampsia. We will conduct complementary analyses in two racially- and geographically diverse multi-center U.S. prospective cohorts: the Collaborative Perinatal Project (n=55,908; 46% white; 47% black) and the NICHD Maternal-Fetal Medicine Units Network High-Risk Aspirin Study (n=917 pregnancies; 33% white, 57% black). First, we aim to determine the independent association between maternal vitamin D status and the risk of sPTB and preeclampsia, and identify the extent to which this association is modified by maternal race. Vitamin D status at d26 weeks' gestation will be assessed using serum 25-hydroxyvitamin D. Second, we will evaluate the independent effect of maternal vitamin D status on maternal inflammation, and identify the extent to which this association is modified by maternal race. Maternal inflammation will be assessed using high-sensitivity C- reactive protein (CRP) measured at d26 weeks' gestation. Finally, we will determine the effect of maternal and fetal/neonatal genetic variation in key vitamin D metabolic loci on maternal vitamin D status, and on the risk of sPTB and preeclampsia. We will study genes whose protein products are directly involved in the metabolism of vitamin D: 25-hydroxylase (CYP27A1), 1a-hydroxylase (CYP27B1), vitamin D binding protein (GC), 24- hydroxylase (CYP24A1), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARA). This project is highly responsive to the NIH Roadmap Initiative, given the confluence of expertise across epidemiologic, clinical, and biological sciences. Moreover, the project is significant because maternal vitamin D status is modifiable. Interventions to improve vitamin D status, such as a moderate increase in sunlight exposure or vitamin D supplementation, are inexpensive, safe, and acceptable to women. Given the high proportion of vitamin D inadequacy among black women, and the profound impact sPTB and preeclampsia have on perinatal morbidity, this project has tremendous capacity to benefit public health. This proposal aims to explore the role of maternal vitamin D status during pregnancy as a risk factor for spontaneous preterm birth and preeclampsia, two adverse pregnancy outcomes that are associated with significant perinatal morbidity. The study hypotheses predict that vitamin D deficiency contributes to the racial disparity in spontaneous preterm birth and preeclampsia. Improving vitamin D status in pregnant women may be a simple strategy for reducing the excess cases of adverse birth outcomes among black women in the United States.