Vitamin D: a link to racial disparities in birth outcomes

描述(由申请人提供)：这项建议将通过探索这些途径背后的新机制，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上的差距。我们把重点放在母亲维生素D上，这是一种以前未被探索过的对怀孕结果的影响。我们已经证明，维生素D缺乏症在整个怀孕期间在黑人女性中普遍存在，在白人女性中明显较少见。此外，新的数据表明，维生素D对炎症和其他已知的分子通路有直接和间接的影响，在自发早产(SPTB)和先兆子痫的发病机制中。因此，维生素D状态是sPTB和先兆子痫的一个未知的危险因素。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代谢相关基因的多态对sPTB和先兆子痫风险的相互作用。我们将在两个种族和地理上不同的美国多中心前瞻性队列中进行互补分析：合作围产期项目(n=55,908；46%白人；47%黑人)和NICHD母婴医学单位网络高风险阿司匹林研究(n=917例怀孕；33%白人，57%黑人)。首先，我们的目标是确定母亲维生素D状态与sPTB和先兆子痫风险之间的独立关联，并确定这种关联被母亲种族改变的程度。妊娠26周时的维生素D状态将使用血清25-羟基维生素D进行评估。第二，我们将评估母亲维生素D状态对母亲炎症的独立影响，并确定这种联系被母亲种族改变的程度。孕妇炎症将使用妊娠26周时测量的高敏C反应蛋白(CRP)进行评估。最后，我们将确定母亲和胎儿/新生儿关键维生素D代谢位点的遗传变异对母亲维生素D状态的影响，以及对sPTB和先兆子痫风险的影响。我们将研究其蛋白产物直接参与维生素D代谢的基因：25-羟基酶(CYP27A1)、1a-羟基酶(CYP27B1)、维生素D结合蛋白(GC)、24-羟基酶(CYP24A1)、维生素D受体(VDR)和维甲酸受体α(RARA)。考虑到流行病学、临床和生物科学方面的专业知识的融合，该项目高度响应NIH路线图倡议。此外，该项目意义重大，因为孕妇的维生素D状态是可以修改的。改善维生素D状况的干预措施，如适度增加阳光暴露或补充维生素D，是廉价、安全和妇女可以接受的。鉴于黑人妇女维生素D缺乏的比例很高，以及肺结核和先兆子痫对围产期发病率的深刻影响，该项目具有巨大的惠及公众健康的能力。公共卫生相关性：这项建议旨在探讨孕妇孕期维生素D状况作为自然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显著的围产期发病率相关。研究假设预测，维生素D缺乏导致了自然早产和先兆子痫的种族差异。改善孕妇的维生素D状况可能是一个简单的策略，可以减少美国黑人女性不良生育结局的过量病例。

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.