广西壮族人群出生缺陷的前瞻性队列研究及先天性心脏病基因-环境交互作用分析

The incidence of birth defects (BD) in Guangxi is much higher than the average of national level. The incidence of congenital heart disease (CHD) which seriously endanger the lives and health of infants is at top among BD. Our preliminary survey found that the incidence of BD in Zhuang ethnic group was relatively higher. The hypothesis is proposed: the epidemic reasons of BD in Zhuang ethnic group may related to some environmental exposure or gene. Very few research on this aspect has been reported so far.This project intends to conduct research on this issue with two stages. First, a prospective cohort study will be conducted among pregnancy couples of Zhuang ethnic group since 3 months before pre-pregnancy to 12 months after postpartum, during this cohort study, suspicous environmental exposure factors will be monitoredin certain time intervels. According to birth outcomes, we will investigate the epidemiological characteristics and and analyze the risk factors associated with birth defects among the Zhuang population. Second, detailed study on the interaction of genes and environment in CHD will be carried out with nested case-control design study. Children with CHD and their parents from the original cohort with birth defects will be selected as the case group, while the control group will be macthed from same group of population who has no birth defects situation during the same period. Single nucleotide polymorphism of Gene linked with cardiac transcription factors will be detected for interactional analysis between the gene and early exposure risk factors at pre-pregnancy stage, aims to identify gene-environment interactions in CHD which will provide foundational knowledge for the prevention and control of CHD in Zhuang population.

广西的出生缺陷（BD）发生率远高于全国水平，其中先天性心脏病（CHD）发生率居于首位。我们的前期调查发现，壮族人群聚集地区BD的发生率相对较高，由此提出假说：广西壮族人群BD的流行状况是否与其环境暴露及基因有关？目前关于这方面的研究鲜见报道。本项目拟分两个阶段开展研究。（1）开展前瞻性出生队列研究：对壮族怀孕夫妇孕前3个月至产后12个月进行定期随访调查其暴露情况，分析壮族人群的BD流行情况及相关危险因素。（2）利用巢式病例对照研究方法对CHD开展基因-环境交互作用研究：队列中CHD患儿及父母作病例组，以匹配正常儿童及其父母作对照组，检测心脏转录因子相关基因单核苷酸多态性，并与其父母孕前孕早期暴露的危险因素作交互作用分析，进一步阐明基因-环境因素交互作用在CHD发病中的作用，为壮族人群BD和CHD的防控提供新的科学依据。

前几年广西出生缺陷的发生率比较高，为了探索广西壮族人群妊娠结局的情况，本项目构建一个较大规模的壮族人群出生队列，并建立了相应的数据库和生物样本库。分析队列中孕妇在孕期中的临床指标如 BMI、甲状腺激素、体重增长、肝功能水平、体育锻炼等对妊娠结局的影响，研究了孕妇血清中多环芳烃（PAHs）的内暴露水平，心脏转录因子Nkx2.5，GATA4和TBX5基因多态性与室间隔缺损(VSD) 遗传易感性的关系，脐带血妊娠高血糖对孕鼠子代心肌血小板反应蛋白-1 表达和细胞凋亡的影响。研究显示：孕中期增重、超重和肥胖是出生巨大儿的危险因素，早期血红蛋白（Hb）浓度与新生儿体重呈正相关，孕晚期 Hb 浓度和孕期 Hb 浓度变化与新生儿体重呈负相关；孕早期贫血、孕期Hb浓度下降幅度过低、孕前体质指数＜18．5kg/m2 和孕期增重不足是小于胎龄儿的危险因素；孕妇妊娠合并轻型α-地中海贫血、谷丙转氨酶水平升高、球蛋白水平升高是新生儿低出生体重儿发生的可能危险因素；孕期运动锻炼与新生儿出生体重和身长的增长均有显著关联。孕期规律参加体育锻炼与较长的新生儿平均相对端粒长度有关；TBX5 基因 SNP 位点 rs883079 与 VSD 的遗传易感性相关；rs883079 位点基因型存在民族差异。壮族妇女及其胎儿暴露于多种致癌性 PAHs， 孕早期母亲高暴露于 PAHs 可能是导致出生缺陷的危险因素；家庭用木材为烹饪燃料 以及未使用厨房通风设备可能会增加孕期妇女 PAHs 的暴露水平；TSP-1 可能通过参与高血糖孕鼠子代心肌细胞凋亡过程导致其心肌损伤而影响心脏发育。本研究结果为壮族人群降低出生缺陷发生率、干预妊娠结局、提高人口质量提供了科学依据。