Research On Screening And Interactions Analysis Of SNPs In Occupational Noise-Induced Deafness Susceptibility Genes

Objectives1.With the analysis strategy of candidate genes,this study is aimed at providing scientific evidences for the establishment of screening methods for Occupational Noise-induced Deafness(ONID)susceptibility genes suitable for Chinese through the screening and verification of Single Nucleotide Polymorphisms(SNPs)in ONID susceptibility genes in Chinese noise-exposed workers.2.By analyzing the gene-gene and gene-environment interactions of SNPs in ONID susceptibility genes,another objective of this study is to comprehensively understand the influence of SNPs in ONID susceptibility genes on the development of ONID in noise-exposed workers,and to provide a theoretical basis for exploring the mechanism of ONID.MethodsIn this study,case-control study was used to conduct occupational epidemiological investigation based on candidate susceptibility gene analysis strategy.1.Data and biological sample collection: The noise-exposed workers who participated in the diagnosis of ONID and occupational physical examination in Guangdong Occupational Disease Prevention and Control Institute and Dongguan Occupational Disease Prevention and Control Center from 2019 to 2021 were selected as the research subjects.Among them,the patients diagnosed as ONID were selected as the case group.The control group chose the noise-exposed workers without hearing loss in high frequency who had no statistical difference with the case group in gender,nationality,cumulative noise exposure(CNE),time of wearing earplugs/earphone.The data were obtained through questionnaire survey,hearing testing,noise detection at the workplace,diagnosis of occupational disease and so on,and venous blood was collected.2.Screening stage: SNPs in ONID candidate susceptible genes were genotyped by SNa Pshot sequencing method,and susceptible SNPs were screened by logistic regression analysis.3.Verification stage: Taqman-MGB probe method was used to verify the screened susceptible SNPs in the new noise-exposed population,and genetic risk score(GRS)was used to evaluate the cumulative effect of genetic risk of susceptible SNPs.4.Interactions analysis: Classification and regression tree(CART)and logistic regression analysis method were used to analyze the gene-gene interaction and gene-environment interaction at SNPs in ONID susceptibility gene.Results1.In the screening stage,83 ONID cases and 83 controls were included.After the correction of relative factors,the genotypes and alleles distribution of 8 SNPs in 61 SNPs in ONID candidate susceptibility gene were significantly different between the two groups and were associated with the risk of ONID under five genetic models(P<0.05).They are CDH23-rs2394795,FAS-rs1468063,FAS-rs2862833,GJB2-rs3751385,PTPRN2-rs10081191,SIK3-rs6589574,STAT3-rs1053023,STAT3-rs1053005.2.In the validation stage,125 ONID cases and 143 controls were included.(1)The genotypes or alleles of 7 SNPs in 8 SNPs in ONID susceptibility genes were significantly associated with the risk of ONID under five genetic models(P<0.05).The results showed that the risk of ONID in CDH23-rs2394795-AA genotype was 2.558 times that in BB genotype(P<0.05),and the risk of ONID in A allele was 1.574 times that in B allele(P<0.05).The risk of ONID in FAS-rs1468063-BB genotype was 1.985 times that in AA+AB genotypes(P<0.05),and the risk of ONID in AA+BB genotypes was 1.859 times that in AB genotype(P<0.05).The risk of ONID in FAS-rs2862833-AA genotype was 2.129 times that in AB+BB genotypes(P<0.05),and the risk of ONID in AA+BB genotypes was 1.760 times that in AB genotype(P<0.05).The risk of ONID in GJB2-rs3751385-BB genotype was 4.253 times that in AA+AB genotypes and was 4.243 times that in AA genotype(P<0.05),and the risk of ONID in AB+BB genotypes was 1.832 times that in AA genotype(P<0.05),and the risk of ONID in AA+BB genotypes was 1.970 times that in AB genotype(P<0.05),and the risk of ONID in B allele was 2.797 times that in A allele(P<0.05).The risk of ONID in PTPRN2-rs10081191-AA+BB genotypes was 1.774 times that in AB genotype(P<0.05).The risk of ONID in STAT3-rs1053023-AB genotype and STAT3-rs1053005-AB genotype was 1.684 times that in AA+BB genotypes(P<0.05).(2)The results of GRS showed that,with the increase of GRS value,the proportion of the cases was gradually higher than that of the controls;the higher the GRS grade,the higher the OR value,that is,the higher the risk of ONID,and there was a significantly positive correlation between ORs value and GRS grade(P=0.020);the risk of ONID in high GRS group(GRS≥8)was2.930 times that in low GRS group(GRS<8)(P<0.05).The above results suggested that there was a significant correlation and genetic cumulative effect between these seven SNPs and ONID susceptibility.(3)The results of CART analysis showed that,in the analysis of gene-gene interaction,CDH23-rs2394795,FAS-rs2862833,GJB2-rs3751385 and STAT3-rs1053023 finally entered the tree.Compared with the subjects carrying GJB2-rs3751385-AA/AB + FAS-rs2862833-AB,the risk of ONID of the subjects carrying GJB2-rs3751385-AA/AB + FAS-rs2862833-AA/BB +STAT3-rs1053023-AB + CDH23-rs2394795-AA/AB increased by 5.360 times(P<0.001).When the subjects carried GJB2-rs3751385-BB,the risk of ONID increased by 6.223 times(P<0.001).In the analysis of gene-environment interaction,CDH23-rs2394795,FAS-rs2862833,GJB2-rs3751385,STAT3-rs1053023,age,CNE,smoking and drinking status finally entered the tree.Compared with the subjects aged <36 years old,the risk of ONID increased by11.444 times when the subjects were aged ≥36 years old +GJB2-rs3751385-AA/AB + FAS-rs2862833-AA/BB + STAT3-rs1053023-AA/BB + smoking(P<0.001);the risk of ONID increased by 9.667 times when the subjects were ≥36 years old + GJB2-rs3751385-AA/AB + FAS-rs2862833-AB + no drinking + CNE<98d B(A)·year(P<0.001);when the subjects were≥36 years old + GJB2-rs3751385-AA/AB + FAS-rs2862833-AA/BB +STAT3-rs1053023-AB + CDH23-rs2394795-AA/AB,the risk of ONID increased by 23.000 times(P<0.001);when the subjects were aged ≥36 +GJB2-rs3751385-BB,the risk of ONID increased by 19.000 times(P<0.001).Conclusions1.This study suggested that CDH23-rs2394795,FAS-rs1468063,FAS-rs2862833,GJB2-rs3751385,PTPRN2-rs10081191,STAT3-rs1053023 and STAT3-rs1053005 were the SNPs of ONID susceptibility genes,which were significantly associated with the risk of ONID,and there was a cumulative effect of genetic risk.2.CDH23-rs2394795,FAS-rs2862833,GJB2-rs3751385 and STAT3-rs1053023 had gene-gene interaction,which is the set(group)of SNPs in ONID susceptible gene.3.There was a gene-environment interaction between the set(group)of SNPs in ONID susceptible gene,age,CNE,smoking and drinking,which can jointly affected the occurrence and development of ONID.