重要炎症细胞因子基因多态性与早产及胎膜早破易感性的关联分析

Premature birth (PTB) has become a major public health concern that has been a threat to the health and life of newborns, with approximately 15 million premature births occurring annually across the globe. Nearly 1.1 million preterm infants were born every year in China, second only to India. 30% of preterm labor were caused by premature rupture of membranes (PROM). The same as with other complex diseases, premature birth and PROM involve both genetic and environmental factors. It has been shown that the important inflammatory cytokines, TNFα, IL-1β, IL-6, TGF-β, IL-l0, IL-8, MCP-1, MIP-1, RANTES and CXCL6, play an important role in the pathogenesis of PTB and PROM. Then we hypothesized that these inflammatory cytokines might be potential candidate susceptibility genes for PTB and PROM. In this study, we will examine whether the functional SNPs are related to the risk of PTB and PROM through case-control association study. And by measuring the level of the inflammatory cytokines in the blood and amniotic fluid of mothers and newborns, functional studies will carry out to explore the function of significantly associated SNPs. The identification of susceptibility genes and SNPs contributing to the risk of PTB and PROM would assist in predicting individual and population risks of PTB and PROM, as well as providing new markers for the prevention and intervention of PTB.

早产一直是威胁新生儿健康和生命的世界性卫生问题。每年全球约有1500万的早产儿，在我国早产儿的出生数量为110万，仅次于印度。早产中有30%由胎膜早破引起，是引起早产的重要因素。与其他复杂性疾病相同，早产和胎膜早破都是遗传和环境因素相互作用的结果。TNFα 、IL-1β、IL-6、TGF-β、IL-l0、IL-8、MCP-1、MIP-1、RANTES和CXCL6等重要炎症因子在早产和胎膜早破发病中具有重要作用，是研究早产和胎膜早破易感性很好的候选基因。我们拟通过病例-对照关联研究，确定这些细胞因子功能SNPs与早产和胎膜早破的发生的关联性，然后通过测定母亲和新生儿血液及羊水微环境中炎症因子的含量差异等功能实验进一步探索显著关联的SNPs的功能，揭示遗传学关联背后蕴含的生物学意义。希望通过此项研究，获得具有应用价值的易感基因和SNPs，为早产的早期预防和干预提供新的标记。

研究MCP-1、RANTES、TNF-α、OAS1、IL-15、IL-1β、MMP-8这7种重要炎症介质基因的SNPs与SPTB遗传易感性的关联性。采用基于候选基因的病例-对照研究，病例组包括753例SPTB新生儿，对照组包括681例足月新生儿。运用传统的PCR-RFLP技术、PCR-测序技术和最新的Sequenom MassARRAY®SNP检测技术分别对MCP-1 G-2518A、RANTES In1.1 T/C、TNF-αG-308A、OAS1 rs10774671、IL-15 rs10833、IL-1βC+3953T和MMP-8 C-799T这7种基因的多态性位点进行SNP分型。结果发现MCP-1 G-2518A、RANTES In1.1 T/C、IL-15 rs10833、IL-1β C+3953T和MMP-8 C-799T，这些SNP位点可以影响SPTB的遗传易感性，OAS1rs10774671和TNF-αG-308A与SPTB的患病风险无显著的遗传学关联。本项研究首次在中国人群中进行大样本的系统的研究（病例组753例-对照组681例）遗传因素对SPTB遗传易感性的影响。而且易感基因和SNP位点的发现对于预防SPTB的发生，阐明SPTB的病因和发病机制具有重要意义。项目执行期间发表标有资助号的SCI论文1篇，另有1篇SCI论文已投稿，项目负责人均为第一作者；发表标有资助号的中文论著3篇，另有3篇已接收，项目负责人均为通信作者。申请了3项专利。