母亲环境烟草烟雾暴露及其代谢酶基因多态性对子代先天性心脏病易感性研究

Congenital heart defects (CHDs) has become the highest birth prevelance of birth defects in China. At present, there is lack of the knowledge about the association betwenn non smoking mothers exposed to environmental tobacco smoke (ETS) and CHDs occurance in their offspring. Because there are some problems in the previous studies, e.g. subjective measure of ETS exposure, being failed to explain the variation in the risk of ETS-related CHDs among different mothers. This study uses case-control study design (inluding 465 cases and 465 controls), and it aims to explore the association of the different level of maternal ETS exposure during the period from 3 months prior to conception to 3 months after conception determined by biomarker in maternal hair (hair nicotine concentration) with CHDs occurrence, and evaluate modified or interaction effect on ETS-related CHDs by considering maternal metabolic genes' genotypes (13 metabolic genes e.g.CYP, GST et al. and 21 SNPs or deletions). This study will confirm the dose-response effect between maternal exposure to ETS and the risk of CHDs, and explore the potential impact of the metabolic enzyme genes polymorphism on the association between ETS and CHD. Thereby the reasons on the variation in the risk of ETS-related CHDs among different mothers will be further revealed. This study will provide more proves for future studies to explore the mechanisms of ETS-related CHDs occurrence, and also scientific basis for early prevention of CHDs.

先天性心脏病(CHDs)已成为我国发病率首位的出生缺陷。目前对非吸烟母亲环境烟草烟雾（ETS）暴露与CHDs之间关联尚认识不足，主要原因是以往研究存在暴露测量主观以及未能解释ETS暴露对CHDs易感性在不同个体间存在变异等问题。本研究采用病例对照设计，通过检测465例病例与465例对照非吸烟母亲头发尼古丁蓄积含量衡量其孕前三个月至孕后头三个月ETS暴露程度，并通过对母体吸烟化学物相关代谢酶基因多态性（细胞色素P450、谷胱甘肽转移酶基因等13个基因21个SNPs或缺失）的测定，进行母亲ETS暴露及代谢酶基因多态性对子代CHDs易感性研究，以探索非吸烟母亲ETS暴露与CHDs发生风险之间的剂量反应关系，评估代谢酶基因多态性对ETS与CHDs关联的效应修饰与交互作用，揭示母亲ETS暴露对子代CHDs易感性在不同个体间产生变异的原因，为探索ETS影响CHDs的内在机制与疾病早期防治奠定理论基础。

【背景与目的】先天性心脏病(CHDs)是我国发病率最高的出生缺陷病种。研究证据表明母亲孕期吸烟暴露能显著增加子代CHDs发生风险，但对环境烟草烟雾（ETS）暴露与CHDs之间关联尚认识不足。本研究将采用人体生物标记物测量母亲孕早期ETS暴露，进而探索母亲ETS暴露及其相关代谢酶基因多态性与CHDs发生之间的关联，为CHDs早期预防以及控烟策略的制定提供科学依据。.【结果】 (1)母亲HNC为0.0923-0.1744 ng/mg、0.1744-0.2961 ng/mg以及≥0.2961 ng/mg的母亲其子代CHDs发生风险分别是参照组（<0.0923 ng/mg）的2.017倍、3.035倍与8.833倍，即母亲HNC越高，其子代CHDs发生风险也越高。(2)母亲GSTP1的SNP位点rs1695等位基因G的频率在病例组中为20.60%，高于对照组的14.47% ，OR值为1.534。其余代谢酶基因SNPs位点的等位基因频率或基因型在病例对照组之间差异均无统计学意义。(3)在相同较高ETS暴露时(HNC>0.1744 ng/mg)，母亲携带EPHX1(rs868966*GG)、GSTP1(rs1695*“GG+GA”或GSTM1基因缺失分别与子代CHDs发生风险增加有关；在相同较低ETS暴露时(HNC≤0.1744 ng/mg)，母亲携带NAT2 rs9987109*“CC+CT” 或rs1208 *“GG+ GA”分别与子代CHDs发生风险增加有关。此外，本研究发现母亲HNC与EPHX1(rs1051740)与UGT1A(rs6717546) 三者之间存在交互作用有统计学意义。母亲携带rs1051740*CC且rs6717546*AA基因型与ETS暴露所致子代CHDs发生风险降低有关；同时，在较高ETS暴露时GSTM1未缺失且携带rs868966*AG基因型的母亲相对于携带对应的其他基因型的母亲其子代CHDs发生风险最低，但母亲HNC与GSTM1(Deletion)与EPHX1(rs868966)三者之间的交互作用未显示出统计学意义（P=0.090）。.【结论】母亲孕早期ETS暴露可能与子代CHDs发生风险增加有关；母亲ETS暴露及其若干代谢酶基因多态性与子代CHDs发生风险之间存在关联，从而初步探索了烟草烟雾暴露导致CHDs的发生风险在个体间产生变异的原因。