噪声性聋易感基因及其突变的鉴定和分子机制研究

Noise induced hearing loss (NIHL) is one of the most common types of sensorineural hearing loss, and has the highest prevalence among all the occupational diseases. Epidemiological and animal research, as well as our preliminary study demonstrates the role of genetic factors in NIHL. Up to date, however, human study for NIHL genetics has been limited to the verification of few candidate genes related to inner ear structure and functions based upon the past studies in animals on ototoxicity and presbycusis, and there is a lack of whole-genome screen and analysis for NIHL susceptibility. In our preliminary work, our team has collected blood and phenotypic information from more than 3000 workers with a long history of noise exposure. By using the second generation of whole exon sequencing technique, we have identified 8 genes and 11 loci of mutation that that are highly related to NIHL. Based upon those development, our proposed study will do sequencing analysis in a fairly enlarged sample in combination with snapshot confirmation in order to fully screen out the candidate genes and their mutations for NIHL genetic susceptibility. In future study, we will take the advantage of our team in zebrafish genetic modulation, hearing evaluation, noise exposure, auditory physiology, inner ear morphology, as well as the establishment and evaluation of NIHL model in mammals. We will identify the genes and mutation loci and establish the gene and mutation map for NIHL genetic susceptibility by full-scale evaluation of the functions and potential ill-causing mechanisms of all NIHL candidate genes and mutations. The identification of such a gene/mutation map will then serve as the guide for the screening of NIHL susceptible individuals.

噪声性聋（noise induced hearing loss，NIHL）是最常见的感音神经性聋之一，位居全球职业病之首。流行病学、动物实验及我们的前期研究均证实遗传因素在NIHL发生中起重要作用。迄今，有关人类NIHL的遗传学研究仅限于与内耳结构与功能相关的少数候选基因的筛查，缺乏全基因组范围内的基因信息分析。本项目组前期完成了3000余例噪声暴露工人的血液及表型资料收集，并采用二代测序技术筛选出与NIHL高度相关的8个基因的11个突变位点。本研究拟在此基础上扩大样本测序并采用Snapshot技术进行验证，以全面筛选NIHL候选易感基因及其突变；利用本项目组在斑马鱼的基因调控、测听及噪声暴露，听觉生理，内耳形态，噪声损伤建模等方面的独特优势，系统评估NIHL候选易感基因及其突变体的功能和致病机制，从而确定中国人群NIHL易感基因及其突变位点, 为尽早开展NIHL易感个体筛查提供重要依据。

噪声性聋（noise induced hearing loss，NIHL）是最常见的感音神经性聋之一，位居全球职业病之首。研究证实遗传因素在NIHL的发生发展中起重要作用。迄今为止，有关人类NIHL的遗传学研究仅限于与内耳结构与功能相关的少数候选基因的筛查，缺乏全基因组范围内的遗传研究。本项目结合高通量测序技术和大样本人群队列，旨在探索遗传因素在噪声性聋易感性中的作用，鉴定中国人群噪声性聋易感基因及其突变位点，解析噪声性聋易感基因及其突变在疾病发生中的分子致病机制。本课题组完成了以下研究工作：（1）建立了16400余人次包含人口信息、听力学数据及血液样本的NIHL生物样本库； （2）通过对样本库的资料及听力学数据分析，明确了我国职业噪声性聋的易感频率、发生及发展规律；（3）基于机器学习算法发展了噪声性聋的预测模型及噪声性聋易感个体的筛选的新策略；（4）利用高通量测序及扩大样本验证等方法，获得19个与NIHL易感性相关的候选基因突变位点，丰富了中国人群NIHL易感基因突变谱；（5）通过实验验证，首次发现PER2、IL-4、AQP9等基因与NIHL相关。本项目建立了全国最大的 NIHL 生物样本库，为 NIHL 的遗传学研究储备资源。结合高通量测序技术及大样本队列对中国人群NIHL基因的鉴定和验证做了开拓性的探索，克服了以往噪声性聋易感性研究的小样本、低通量、仅集中于少数候选基因的不足，使噪声性聋遗传学研究在方法学上更加客观严谨；通过对候选基因的致病机制的研究，推动我国 NIHL遗传学研究的进步，为NIHL高位人群和易感人群的筛查、为NIHL 的防治及药物研发提供重要的理论基础及实验依据。