DNA甲基化与职业性噪声听力损失关联的病例对照研究

A case-control study on the relationship between DNA methylation and occupational noise hearing loss

目的探讨DNA甲基化与职业性噪声听力损失的关联。方法采用病例对照研究方法,从2006年建立的某钢铁厂噪声作业工人研究队列中,选择职业性噪声暴露听力损失病例为病例组,职业性噪声暴露听力正常人群为对照组。共纳入60例调查对象,其中病例组和对照组各30例。应用850K全基因组DNA甲基化芯片技术检测甲基化水平,采用R包champ进行差异甲基化位点(DMP)的显著性检验,采用R包champ的Bumphunter算法,进行差异甲基化区域(DMR)分析。采用clusterProfiler对基因列表进行GO和KEGG通路富集分析。结果两组研究对象在双耳高频平均听阈差异具有统计学意义(P<0.05),在年龄、吸烟情况、饮酒情况、高血压情况、体育锻炼和累积噪声暴露量方面差别均无统计学意义。DMP和DMR分析结果显示,病例组和对照组中检测了713875个位点,差异显著的甲基化位点439个,占比0.06%;检测了650个区域,差异显著的甲基化区域72个,占比11.08%。GO富集分析结果显示,与对照组相比,病例组在中枢神经系统投射神经元轴突发生、中枢神经系统神经元发育、中枢神经系统神经元轴索发生和中枢神经系统神经元分化4个通路差异具有统计学意义。KEGG富集分析结果显示,与对照组相比,病例组和对照组在鞘脂代谢、醛固酮的合成和分泌、初级胆汁酸生物合成通路差异具有统计学意义。结论职业性噪声听力损失的发生可能与中枢神经系统投射神经元轴突发生、中枢神经系统神经元发育、中枢神经系统神经元轴索发生、中枢神经系统神经元分化、鞘脂代谢、醛固酮的合成和分泌、初级胆汁酸生物合成等通路相关的基因表达调控或代谢有关的基因甲基化状态有关。

Objective To explore the relationship between DNA methylation and occupational noise-induced hearing loss.Methods A case-control study was conducted.People with hearing loss induced by occupational noise were recruited as the case group and those with normal hearing but still exposed to occupational noise were recruited as the control group.A total of 60 participants were included,of which 30 participants were in the case group and 30 in the control group.The methylation level was detected by 850k genome-wide DNA methylation chip technology.The significance of differential methylated position(DMP)was tested by R-packet‘Champ’.The differential methylated region(DMR)was analyzed by using Champ′s Bumphunter algorithm.Cluster profiler was used to analyze the gene list for GO and KEGG pathway enrichment.Results There was significant difference between two groups in binaural high-frequency average hearing threshold(P<0.05),but there was no significant difference in age,smoking,drinking,hypertension,physical exercise and cumulative noise exposure.The results of DMP and DMR analysis showed that 713875 sites were detected in the case group and the control group,and 439 methylation sites with significant difference,accounting for 0.06%;650 regions were detected,and 72 methylation regions with significant differences,accounting for 11.08%.Compared with the control group,the results of GO enrichment analysis showed that the case group had statistically significant differences in four pathways:axogenesis of projection neurons in the central nervous system,neuronal development in the central nervous system,axogenesis of neurons in the central nervous system and neuronal differentiation in the central nervous system.KEGG enrichment analysis showed that there were significant differences in sphingolipid metabolism,aldosterone synthesis and secretion,primary bile acid biosynthesis pathway between the case group and the control group.Conclusion The occurrence of occupational noise-induced hearing loss may be related to the regulation of gene expression related to axogenesis of projection neurons in the central nervous system,development of neurons in the central nervous system,axogenesis of neurons in the central nervous system,differentiation of neurons in the central nervous system,sphingolipid metabolism,aldosterone synthesis and secretion,primary bile acid biosynthesis and gene methylation related to metabolism.