Association Between FOXO3 Gene Polymorphisms And Susceptibility To Noise-induced Hearing Loss

Objective To explore the association between FOXO3 gene polymorphisms(rs2802292,rs10457180,rs12206094 and rs12212067)together with their haplotypes and the genetic susceptibility to noise-induced hearing loss in noise-exposed workers of Han nationality.Methods 1.Subjects A total of 2689 noise workers from a large chemical fiber company in Jiangsu Province were selected as screening targets and screened according to uniform inclusion and discharge standards.Using the labor hygiene survey and the case-control study method,the subjects were divided into noise-induced hearing loss group(case group,566 cases)and normal hearing group(control group,566 cases)matched by age,gender,smoking,drinking,noise exposure level and years,according to the results of pure tone air conduction hearing test.2.Questionnaire and pure-tone audiometry test On-site enquiries were conducted on the subjects using a special questionnaire.The survey included general information,smoking and drinking status,occupational history with noise,use of personal protective equipment,and family history of hereditary deafness.Pure-tone audiometry test for the binaural 500 HZ and 1,2,3,4,6 KHz was conducted by physicians referred to the GBZ 49-2014 "Occupational Deafness Diagnostic Criteria" after subjects detaining from the noise environment for at least 48 hours.3.Measurement of noise exposure According to the requirements of GBZ/T 189.8-2007 "Measurement of Physical Factors in Workplace-Part 8: Noise",the noise intensity of workshop and the personal exposure dose of noise were measured by using Quest Sound Pro sound level meter and Quest Noise Pro-DL multi-function personal noise dosimeter respectively.4.SNPs selection and genotyping 2 ml of fasting peripheral venous blood of subject was collected,and genomic DNA was extracted using the Tiangen Blood Genomic DNA Extraction Kits(centrifugal column type)according to the instruction.Four SNPs of the FOXO3(namely rs2802292,rs10457180,rs12206094 and rs12212067)were screened by reviewing the NCBI dbSNP database(http://www.ncbi.nlm.nih.gov/SNP)and relevant literatures.These SNPs were genotyped by TaqMan-PCR technology,and the distribution of genotypes between case group and control group was compared.Results 1.Demographic characteristics of subjects A total of 1132 subjects were screened in this study,of which case group and control group each accounted for half.There were no statistically significant differences in age,gender,smoking,drinking,years exposed to noise,and noise exposure levels between these two groups,with P values greater than 0.05.While the hearing threshold shift level of the case group(35.77±9.86 dB)was 2.55 times of that of the control group(14.02±4.17 dB),and the difference was statistically significant(P<0.001).2.Hardy-Weinberg test The genotype distribution of each SNP in the control group was consistent with the Hardy Weinberg equilibrium,P>0.05.3.Multivariate analyses of FOXO3 SNPs with the risk of NIHL The co-dominant model,dominant model(except rs12206094),recessive model and allelic model of rs2802292,rs10457180,and rs12206094 were statistically different in the case group and control group,P<0.05.After adjusting for age,gender,smoking and alcohol consumption,the rs2802292 G allele,rs10457180 G allele and rs12206094 T allele were associated with an increased risk of NIHL with OR and its 95% confidence interval for 1.43(1.18-1.74)、1.43(1.18-1.75)and1.31(1.04-1.64)respectively.Results of hierarchical analysis showed that the rs2802292 GT/GG genotype interacted with exposure noise age;the rs10457180 AG/GG genotype interacted with exposure noise age and low levels of noise exposure.Results of multi-factor dimensionality reduction analysis showed that there may be an interaction between the genotypes of rs10457181,rs2802292 and rs12206094 for the risk of NIHL,OR=1.53(1.20-1.94).4.Association between the haplotypes of FOXO3 SNPs with NIHL risk The GAC haplotype of FOXO3 gene was statistically different between the case group and the control group,P=0.039.Comparing with individuals carrying the TAC haplotype,the risk of NIHL was increased in individuals carrying the GAC haplotype,OR=1.27(1.01-1.59).Conclusions 1.The genetic polymorphisms of the FOXO3 gene is associated with the susceptibility of NIHL,and rs2802292 G,rs10457180 G,and rs12206094 T may be risk factors for NIHL;2.The association between the genetic polymorphisms of the FOXO3 gene and the susceptibility of NIHL is also influenced by gene-environment interactions and gene-gene interactions.GT/GG genotype of rs2802292 and AG/GG genotype of rs10457180 interact with noise exposure to increase the risk of NIHL;3.The GAC haplotype of the FOXO3 gene is associated with an increased risk of NIHL and has potential to be one susceptibility biomarker for NIHL.