[Elucidating the gene-environment interplay in risk factors for Age-related hearing loss]

Objective:To investigate the associations of genetic factors, environmental exposures, and their interactions with the risk of age-related hearing loss（ARHL）. Methods:This case-control study utilized data from the UK Biobank and meta-analyses. Multivariable logistic regression models were employed to analyze the main effects of environmental exposures. A polygenic risk score（PRS） was constructed to assess genetic susceptibility. Gene-environment interactions were investigated by including multiplicative interaction terms and conducting PRS-stratified analyses. All analyses were adjusted for demographic, educational, income, lifestyle, and comorbidity covariates, with P-values corrected using the False Discovery Rate（FDR） method. Results:The study included 162 010 participants（20 660 cases; 141 350 controls）. Analysis of environmental main effects identified hard water as exhibiting the strongest hazardous effect（OR=1.09, 95%CI 1.07-1.12）. Both calcium carbonate（OR=1.07, 95%CI 1.05-1.09） and calcium concentration（OR=1.03, 95%CI 1.01-1.05） were risk factors, while magnesium concentration（OR=0.95, 95%CI 0.93-0.97） exhibited a protective effect. Air pollutants were associated with increased risk, whereas greenspace, blue space, and natural environments demonstrated protective effects. Genetic-environment interaction analysis revealed no statistically significant interactions for any of the environmental factors with the PRS. Stratified analysis by PRS tertiles indicated that the hazardous effect of calcium carbonate concentration was highest in the intermediate genetic risk group（OR=1.15, 95%CI 1.11-1.20） compared to the low（OR=1.10, 95%CI 1.02-1.18） and high（OR=1.12, 95%CI 1.04-1.20） genetic risk groups. Conclusion:This study systematically demonstrates the independent role of environmental factors in ARHL. High-calcium water and air pollution are identified as significant risk factors, while natural environments are protective. The effect of environmental exposures operates independently of an individual's genetic background. Furthermore, individuals with intermediate genetic risk may be more susceptible to calcium carbonate exposure in water.