Vitamin D: a link to racial disparities in birth outcomes

描述（由申请人提供）：本提案将通过探索这些途径背后的新机制来解决我们对早产和先兆子痫中棘手的种族差异的理解差距。我们专注于母体维生素D，这是一种以前未被探索的对妊娠结局的候选影响。我们已经证明，在整个怀孕期间，黑人妇女普遍缺乏维生素D，而白人妇女则明显不那么普遍。此外，新的数据表明，维生素D在自发性早产（sPTB）和子痫前期的发病机制中对炎症和其他已知的分子途径有直接和间接的影响。因此，维生素D水平是sPTB和子痫前期的一个未被探索的危险因素。本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域不同的美国多中心前瞻性队列中进行补充分析：围产期合作项目（n=55,908；白人46%；黑人47%）和NICHD母胎医学单位网络高危阿司匹林研究（n=917例妊娠；白人33%，黑人57%）。首先，我们的目标是确定母亲维生素D水平与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母亲种族的影响。使用血清25-羟基维生素D来评估妊娠第26周时的维生素D水平。其次，我们将评估母体维生素D水平对母体炎症的独立影响，并确定这种关联在多大程度上受母体种族的影响。在妊娠26周时，使用高灵敏度C反应蛋白（CRP）来评估母体炎症。最后，我们将确定母体和胎儿/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状态的影响，以及对sPTB和先兆子痫风险的影响。我们将研究直接参与维生素D代谢的蛋白产物的基因：25-羟化酶（CYP27A1）、1a-羟化酶（CYP27B1）、维生素D结合蛋白（GC）、24-羟化酶（CYP24A1）、维生素D受体（VDR）和维甲酸受体α (RARA)。鉴于流行病学、临床和生物科学的专业知识融合，该项目高度响应NIH路线图倡议。此外，该项目意义重大，因为母亲的维生素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、安全且妇女可接受的。鉴于黑人妇女维生素D缺乏的比例很高，以及sPTB和先兆子痫对围产期发病率的深远影响，该项目具有巨大的公共卫生效益。公共卫生相关性：本研究旨在探讨妊娠期间孕妇维生素D水平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相关。该研究假设，维生素D缺乏会导致自发性早产和先兆子痫的种族差异。提高孕妇的维生素D水平可能是减少美国黑人妇女不良分娩结局的一个简单策略。

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.