孕期维生素D缺乏致儿童过敏性疾病的出生队列和表观遗传机制研究

The prevalance of Vitamin D (VitD)deficiency in pregnancy is about 60% in China. Meanwhile, the prevalance of children's allergy disease is up to 40%. Overseas research shows that VitD in pregnancy is associated with allergic diseases in children, but the exploration of the mechanism still remains at the stage of the experimental research or within the scope of minority population study of postnatal VitD.The evidence shows that the immune response mode is estabished in the fetal period. Accordingly we believe that: the impact of prenatal VitD on immune system is even greater and more direct than that of postnatal. Reported in the literature: VitD can change methylation transferase (DNMT) activity. Our previous study found that VitD deficiency in cord blood significantly increased the promotor methylation of IL-12.Thus,we hypothesize: VitD deficiency in pregnancy may induce the function of the cytokines changed by affectting the methylation of IL-12,IFN-γand Foxp3, the key genes in the immune regulation loop, then trigger Th1/Th2 imbalance and cause the change of fetal immune response mode. Applying the first cohort study of VitD during pregnancy in our country, with an intervention studies in animals, this research will focus on the regulation of Th1/Th2 by the induction of dendritic cells, the mutual inhibition of Th1 and Th2, and the feedback regulation of Treg cell. It is the first attempt at home and abroad to study the effects of VitD in pregnancy on the muti-gene methylation and fetal immune response. Furthermore,the appropriate VitD level will be assessed, which will provide the basis for the recommended intake of VitD during pregnancy.

我国孕妇维生素D(VitD)缺乏约为60%，儿童过敏性疾病高达40%。国外研究表明孕期VitD与儿童过敏性疾病有关,但机制研究尚停留在实验或少数人群出生后的研究。证据表明免疫应答模式的建立开始于胎儿期，据此我们认为：胎儿期VitD对免疫系统的影响比生后的影响更为直接深远。文献报道：VitD能改变甲基化转移酶活性；我们前期研究发现脐血VitD缺乏使IL-12启动子甲基化明显上升。由此我们提出假说：孕期VitD缺乏可能通过影响免疫调节关键基因IL-12、IFNγ、Foxp3的甲基化致其功能改变，引发Th1/Th2 失衡而致免疫应答模式改变。本课题将建立国内首个孕期VitD出生队列，并结合动物干预研究，从树突状细胞诱导、Th1和Th2互为抑制、Treg细胞反馈调节Th1/Th2 的角度，在国内外率先研究VitD影响胎儿免疫应答的多基因甲基化机制；并评估适宜孕期VitD水平，为推荐量修订提供依据。

我国孕妇维生素D (VitD)缺乏率约为60%，而儿童过敏性疾病的发生率高达40%。国外研究表明孕期VitD状况与儿童过敏性疾病相关，但其机制研究仍停留在实验研究或少数人群出生后的研究。基于上海市出生队列研究，我们发现上海市孕妇脐血维生素D水平主要与出生季节及孕期维生素D的补充相关。同时我们发现脐血维生素D水平与脐血IgE水平呈非线性相关关系，且存在阈值效应。我们进一步分析发现：孕期维生素D水平与儿童过敏性疾病的发生存在非线性相关关系，并且孕期维生素D对儿童过敏的影响受基因多态性的调节。另外，脐血维生素D水平与儿童2岁时过敏性疾病的发生呈“U”型关系，25(OH)D < 20 ng/L 或者25(OH)D > 30ng/L都增加过敏性疾病发生的风险，尤其对于食物过敏的影响更为明显。关于表观遗传机制的研究，我们通过建立孕期维生素D缺乏的SD大鼠模型发现：孕期维生素D缺乏通过影响DNA甲基化酶（DNMT）活性导致IFN-γ基因的高甲基化，进而影响大鼠Th1/Th2平衡状态，导致免疫失衡，这可能是过敏性疾病发生的机制之一。