Vitamin D: a link to racial disparities in birth outcomes

描述（由申请人提供）：该提案将通过探索这些途径的新机制来解决我们对早产和先兆子痫中难以解决的种族差异的理解中的差距。我们专注于母体维生素D，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缺乏症在整个怀孕期间在黑人妇女中普遍存在，而在白色妇女中则明显不常见。此外，新的数据表明，维生素D对自发性早产（sPTB）和先兆子痫发病机制中的炎症和其他已知分子途径具有直接和间接的影响。因此，维生素D状态是sPTB和先兆子痫的一个未探索的风险因素。这项生殖流行病学研究的目的是阐明母体维生素D状态、炎症和维生素D代谢相关基因多态性与sPTB和先兆子痫风险之间的相互作用。我们将在两个种族和地理上多样化的多中心美国前瞻性队列中进行补充分析：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和先兆子痫风险之间的独立关联，并确定这种关联在多大程度上受到母体种族的影响。将使用血清25-羟基维生素D评估妊娠d26周时的维生素D状态。其次，我们将评估母体维生素D状况对母体炎症的独立影响，并确定这种关联在多大程度上被母体种族所改变。将使用在妊娠第26周测量的高敏C反应蛋白（CRP）评估母体炎症。最后，我们将确定关键维生素D代谢位点的母体和胎儿/新生儿遗传变异对母体维生素D状态以及sPTB和先兆子痫风险的影响。我们将研究其蛋白质产物直接参与维生素D代谢的基因：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）。鉴于流行病学、临床和生物科学专业知识的融合，该项目对NIH路线图倡议高度响应。此外，该项目意义重大，因为产妇的维生素D状况是可以改变的。改善维生素D状况的干预措施，如适度增加阳光照射或补充维生素D，是廉价，安全和可接受的妇女。鉴于黑人妇女中维生素D不足的比例很高，以及sPTB和先兆子痫对围产期发病率的深远影响，该项目具有极大的能力，有利于公共卫生。公共卫生相关性：本提案旨在探讨妊娠期间母体维生素D状态作为自发性早产和先兆子痫的危险因素的作用，这两种不良妊娠结局与围产期发病率显著相关。研究假设预测，维生素D缺乏导致自发性早产和先兆子痫的种族差异。改善孕妇的维生素D状况可能是减少美国黑人妇女不良出生结果的一个简单策略。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.