基于队列的职业性噪声听力损失易感性生物标志物研究

Exposure to occupational noise is the main cause which induced hearing loss, so the primary prevention is the key of prevention and control occupational noise-induced hearing loss. In the present study, the association among exposure to occupational noise, susceptibility biomarker and hearing loss based on the cohort exposed to occupational noise was analyzed using the methods combined cohort study, case-only study with laboratory investigation. Test and verify the hypothesis that the key mechanism of noise-induced hearing loss lies on abnormality in the aspects of ATP, oxidative stress and mitochondria and that crowd noise susceptibility may be association with the genetic polymorphisms in ATP, oxidative stress and mitochondria. In order to look for the susceptibility biomarker of occupational noise-induced hearing loss, the cumulative noise exposure for workers exposed to noise were systematically assessed, and 33 single nucleotide polymorphisms in 15 genes in the three pathways of ATP, oxidative stress and mitochondria were genotyped and the cumulative incidence of occupational noise-induced hearing loss were analyzed according to different genotype. The association among different genotype, length of service when noise-induced hearing loss was occurrence and the cumulative noise exposure were analyzed using the survival analysis including Cox regression model, etc.. In this study, in order to provide the crucial scientific basis and appropriate technology for protecting health of workers exposed to noise, the susceptibility biomarkers of occupational noise-induced hearing loss on the basis of the two aspects including cohort study and case-only study were discovered and verified, and the crowd validation and translational application for the above susceptibility biomarkers were conducted.

职业性噪声暴露是导致听力损失的重要原因，第一级预防是防治工作关键。本研究在建立职业噪声暴露队列人群基础上，采用队列研究、单纯病例研究与实验室研究相结合的方法，研究职业性噪声暴露、易感性标志物和听力损失三者之间关系。验证ATP、氧化应激和线粒体异常是职业性噪声听力损失发病的关键，人群噪声易感与ATP、氧化应激和线粒体基因多态性有关的假设。对噪声作业工人进行系统的累积暴露量评估，对ATP、氧化应激和线粒体三个通路的15个候选基因的33个多态位点进行检测，分析不同基因型的职业性噪声听力损失累积发病率，寻找职业性噪声听力损失易感性生物标志物；使用COX回归模型等生存分析技术分析各个多态位点的基因型与噪声性听力损失发病工龄和累积噪声暴露量的关系，从队列研究和单纯病例研究两个方面寻找和验证职业性噪声听力损失易感性生物标志物，并进行人群验证及转化应用，为保护噪声作业工人健康提供重要科学依据和适宜技术。

本研究建立在职业噪声暴露队列人群基础上，采用队列研究、巢式病例-对照研究、单纯病例研究与分子生物学研究相结合的方法，研究职业性噪声暴露、易感性标志物和听力损失三者之间的关系。基于对7445名噪声作业工人进行系统的累积暴露量评估，通过阶段Ⅰ的病例对照研究（阶段Ⅰ1纳入263例病例、462例对照，阶段Ⅰ2纳入102例病例、216例对照，阶段Ⅰ1+Ⅰ2纳入365例病例和678例对照）和阶段II的队列人群验证研究，对41个候选基因的231个多态位点进行检测，分析噪声作业工人的职业性噪声听力损失发病特征，寻找并验证职业性噪声听力损失易感性生物标志物。结果发现，钢铁厂噪声作业工人噪声性听力损失发病率为6.23%，噪声性听力损失的发生与累积噪声暴露量、性别、年龄、文化程度、吸烟、饮酒及接触高温有关。阶段Ⅰ研究发现，EYA4基因rs3813346位点、ATP6V1B2基因rs10503675位点、ATP6V1B2基因rs11204100位点、DNAH8基因rs874808位点、DNAH8基因rs1738254位点、ATP2B2基因rs2289273位点、ATP2B2基因rs751122位点、PCDH15基因rs11004085位点、HSF1基因rs35253356位点、HSPA1B 基因rs2763979位点和TECTA基因rs10502247位点可能与噪声听力损失相关。阶段II中，多元非条件logistic回归分析发现，DNAH8基因的rs1738254位点和CDH23基因的rs11592462位点可能是噪声听力损失易感性的危险因素；采用COX’s比例风险回归分析随着接噪工龄的增加个体在不同的基因型下对噪声听力损失的易感性变化后发现，DNAH8基因中rs1678674和rs1678729位点可能在噪声听力损失的发展过程中起到保护效应，CDH23基因的rs11592462位点可能是噪声听力损失的危险因素。研究表明，DNAH8基因的rs1678674位点和rs1678729位点与CDH23基因的rs11592462位点与中国人群中噪声听力损失的发生有关，可作为职业性噪声听力损失易感性生物标志物。