乙肝母婴传播的遗传易感基因与社会文化生态因素的交互作用及其机制研究

There are about two million newborns tested HBsAg positive every year due to mother-to-child transmission. It directly has an impact on the quality of newborns and has attracted great attention of state and government, so the research which focuses on the mechanism of susceptibility to mother-to-child transmission of HBV is very urgent and significant. To further explore the epidemic characteristics, occurrence trends, key influencing factors and varying pattern of susceptibility to mother-to-child transmission of HBV, our study aims to investigate the impact of genetic factors (SLC10A1, HLA, Toll-like receptors, IFN-α/γ, TNF-α, IL and ADIPOQ, etc.) and socioculture ecological factors (smoking/passive smoking, drinking, sleep status, diatery structures, nutrition intake and drug use, etc.) on the susceptibility to mother-to-child transmission of HBV. Futher more, we will explore the interaction of these genes and sociocultural ecological factors and its impacts on the risk degree, mechanism and varying pattern of susceptibility to mother-to-child transmission of HBV. Form the perspective of biomedicine and sociology, on the basis of the established birth cohort, combining field research with experiment research, our study intends to adopt a case-control study to achieve above purposes. Preventive strategies will be made based on the research results to decrease the rate of mother-to-child transmission of HBV. In conclusion, this study is of great significance to the Healthy China and socioeconomic development.

我国每年约有200万新生儿因母婴传播在出生时就携带HBV，直接影响到出生人口素质，已引起国家和政府的高度重视。因此，开展乙肝母婴传播的遗传易感性机制研究十分重要和紧迫。为了进一步探讨乙肝母婴传播的流行特点、发生趋势及易感性的关键影响因素和变化规律，本研究拟从生物医学和社会学的视角，在已建立的出生队列研究基础上，以现场研究和实验研究相结合，采用病例-对照研究方法，探讨遗传易感基因（SLC10A1、HLA、Toll受体、IFN-α/γ、TNF-α、IL和ADIPOQ等）和社会文化生态因素（吸烟/被动吸烟、饮酒、睡眠状况、饮食结构、营养摄入和药物使用等）对乙肝母婴传播易感性的影响及作用；探索遗传易感基因和社会文化生态因素的交互作用及其对乙肝母婴传播易感性的作用、机制及变异规律，在此基础上提出干预策略，以减少母婴传播的发生率，对促进健康中国及社会经济发展均具有巨大的意义。

中国的HBV宫内感染仍处于较高水平，是慢性乙型肝炎持续存在的主要原因之一。研究内容：①HBV宫内感染的影响因素及遗传易感性基因②RLR-MAVS和cGAS-STING信号通路基因与宫内传播关联性③基因与环境因素的交互作用对宫内传播的影响。结果：①1529名HBsAg阳性孕妇分娩的1544名新生儿中，HBV宫内感染的发生率为7.1%。HBeAg阳性孕妇分娩的新生儿宫内感染的风险更高；HBV DNA阳性孕妇分娩的新生儿发生宫内感染风险是HBVDNA阴性的2.96倍；宫内感染率随着孕妇孕晚期HBV DNA载量的升高而升高。②携带TLR3 rs3775291 CT、TT基因型的新生儿宫内感染发生的风险较携带CC基因型的新生儿低。携带TLR4 rs1927914 CT基因型与携带TT、CC基因型的新生儿相比，宫内感染风险低（32.43%vs.51.35%，OR=0.45，95%CI：0.21-0.97）。携带TLR3 rs3775291 CT或TT基因型较携带CC基因型的母亲，其新生儿宫内感染风险低。识别SNP导致的遗传易感性差异，以期早期发现HBV宫内传播的高危人群。③RIG-I/MAVS通路中， INTS10 rs28413168位点携带CC/CG基因型的新生儿宫内传播发生风险增加了100%。cGAS-STING通路中，新生儿携带MB21D1 rs311678 GG/AG的宫内传播风险显著低于AA基因型（OR=0.48, 95% CI: 0.30-0.78; P = 0.003）。研究结果为探索影响乙肝宫内传播提供了新线索。④INTS10 rs28413168和 IL10 rs1800872基因多态性与HBeAg之间存在相加交互作用。MB21D1 rs311678基因多态性与HBV DNA之间存在相加交互作用（AP = 0.41, 95% CI: 0.07-0.75)。MB21D1 rs311678多态性与分娩方式间存在相加交互作用（RERI = 4.14, 95% CI: 0.43-7.84; AP = 0.56, 95% CI: 0.28-0.84; SI = 2.84, 95% CI: 1.14-7.04)。本研究系统探讨了基因-环境交互作用对宫内传播发生的影响，为今后采取有效的阻断措施降低我国HBV慢性携带率做出重大贡献。