Study On Association Between Ca²⁺ Signaling Pathway-related Gene Polymorphism And Age-related Hearing Loss

Objective:Age related hearing loss（ARHL）was a common chronic disease in the elderly.ARHL was affected by genetic and environmental factors.Many studies at home and abroad have discussed the heritability and related genes of ARHL,but the correlation between Ca²⁺signaling pathway-related genes and ARHL has not been fully studied.This study investigated the association between the single nucleotide polymorphism（SNP）of Ca²⁺signaling pathway-related gene and ARHL,and provided clues for the genetic mechanism of ARHL.Methods:In this study,two communities in Chengyang District of Qingdao were selected as the investigation site,and the Han unrelated individuals aged 60 and over with ARHL in the community were selected as the case group.The control group used the 1:1matching method to select the Han unrelated individuals with the same age and gender as the case group and from the same community with normal hearing.The basic information of the subjects was obtained through questionnaire survey,the hearing level of the subjects was obtained through pure tone audiometric examination,and the blood samples were collected for blood biochemical test.Hearing level was judged by pure tone average（PTA）of 0.5k Hz,1.0k Hz,2.0k Hz,and 4.0k Hz of the better hearing ear.In other words,PTA of the better hearing ear≤25d B HL was the control group,and PTA≥25d B HL was the case group.Finally,402 subjects were included,including 201 in the case group and201 in the control group.According to Hap Map and 1000 Genomes Project database,4Ca²⁺signaling pathway-related genes and 31 SNPs were selected,including 6 SNPs in CCKAR,12 SNPs in PRKCA,7 SNPs in CACNA1C and 6 SNPs in TRPM1.Mann Whitney U test andχ² test were used to compare the basic situation between the case group and the control group.Hardy Weinberg Equilibrium test is used to verify whether each SNP conforms to Hardy Weinberg Equilibrium.Theχ²test was used to compare the genotype and allele distribution of the SNP between the case group and the control group.The odds ratio（OR）and 95%confidence interval（CI）of codominant,additive,dominant,recessive and superdominant genetic models of SNP were obtained by conditional logistic analysis,to explore the relationship between Ca²⁺signaling pathway-related gene polymorphism and ARHL.The Ca²⁺signaling pathway-related gene score was calculated by gene score method,and the correlation between Ca²⁺signaling pathway-related gene score and ARHL was discussed by conditional logistic regression.The multiplicative interaction model of conditional logistic regression was used to study the relationship between the multiplicative interaction of Ca²⁺signaling pathway-related gene score and environmental factors（smoking,drinking,diabetes,hypertension）and ARHL.Results:1.The basic situation of the subject The results showed that PTA in the case group was significantly higher than that in the control group（P<0.01）.2.Hardy Weinberg Equilibrium test All SNPs were consistent with Hardy Weinberg Equilibrium（P>0.05）.3.Comparison of genotype and allele frequency of Ca²⁺signaling pathway-related genes The genotype distribution of rs17846984 of CCKAR was different between the two groups（P<0.05）.The genotype and allele frequency distribution of rs216008 of CACNA1C were different between the two groups（P<0.05）.4.Adjusted for smoking,passive smoking,drinking,diabetes,hypertension and dizziness handicap situation,the results of codominant and dominant genetic model analysis of rs17846984 of CCKAR showed that compared with CC genotype,people with CT（OR=0.589,95%CI:0.372-0.934）and（CT+TT）（OR=0.643,95%CI:0.415-0.995）genotype had a lower risk of ARHL;analysis of superdominant genetic model found that compare with（CC+TT）genotype,people with CT（OR=0.582,95%CI:0.369-0.920）genotype had a lower risk of ARHL.The results of codominant and dominant genetic model analysis of rs2286674 of PRKCA showed that compared with AA genotype,people with AG（OR=0.609,95%CI:0.395-0.938）and（AG+GG）（OR=0.641,95%CI:0.428-0.960）genotype had a lower risk of ARHL;the results of superdominant genetic model analysis showed that compared with（AA+GG）genotype,people with AG（OR=0.646,95%CI:0.430-0.970）genotype had a lower risk of ARHL.The results of codominant and dominant genetic model analysis of rs8464 of PRKCA gene showed that compared with CC genotype,people with CA genotype（OR=2.005,95%CI:1.048-3.837）and（CA+AA）genotype（OR=2.016,95%CI:1.057-3.846）had an increased risk of ARHL;the results of additive genetic model analysis showed that this rs8464 was associated with ARHL（OR=1.957,95%CI:1.051-3.647）;the results of superdominant genetic model analysis showed that compared with（CC+AA）genotype,people with CA（OR=1.969,95%CI:1.032-3.757）genotype had an increased risk of ARHL.The results of superdominant genetic model analysis of rs9909004 of PRKCA showed that compared with（CC+GG）genotype,CG people with genotype had a lower risk of ARHL（OR=0.631,95%CI:0.412-0.966）.The results of codominant and dominant genetic model analysis of rs61687889 of PRKCA showed that compared with GG genotype,people with GA（OR=0.565,95%CI:0.339-0.942）and（GA+AA）（OR=0.612,95%CI:0.381-0.982）genotype had a lower risk of ARHL.The results of codominant and dominant genetic model analysis of rs216008 of CACNA1C showed that compared with CC genotype,people with CT,TT（OR=0.564,95%CI:0.352-0.903;OR=0.495,95%CI:0.254-0.966）and（CT+TT）（OR=0.548,95%CI:0.349-0.860）genotype had a lower risk of ARHL;the results of additive genetic model analysis showed that rs216008 was associated with ARHL（OR=0.668,95%CI:0.485-0.921）.5.Correlation between Ca²⁺signaling pathway-related gene score and ARHL After adjusting for smoking,passive smoking,drinking,diabetes,hypertension and dizziness handicap situation,multivariate conditional logistic regression analysis showed that PRKCA gene score（OR=1.078,95%CI:1.022-1.136）,CACNA1C gene score（OR=0.782,95%CI:0.662-0.924）and Ca²⁺signal pathway-related total gene score（OR=0.500,95%CI:0.363-0.689）were associated with ARHL.6.Analysis of the multiplicative interaction between Ca²⁺signaling pathway-related gene score and smoking,drinking,diabetes and hypertension Further interaction analysis showed that there was no multiplicative interaction between PRKCA,CACNA1C and Ca²⁺signal pathway-related total gene score and environmental factors.Conclusion:The gene polymorphism of Ca²⁺signaling pathway-related gene is related to ARHL,which may be a factor affecting ARHL.This study provides a basis for finding the susceptible population of ARHL in the elderly population,and also provides clues for exploring the genetic mechanism of ARHL.