Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes.

Abstract

Background: Age-related hearing loss (ARHL) is a common sensory disorder with significant public health implications. However, few effective treatment options are available. Mendelian randomization (MR) has been used to repurpose existing drugs and identify new therapeutic targets. Therefore, we performed a systematic genome-wide MR of drug-eligible individuals to explore potential therapeutic targets for ARHL.

Methods: We obtained data on the expression quantitative trait locis (eQTLs) of druggable genes, which were then subjected to two-sample MR analyses and co-localisation analyses with data from the ARHL genome-wide association study to identify genes highly associated with ARHL. Additionally, we conducted phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking to help develop more effective and targeted therapeutic treatments.

Results: Overall, the MR analysis of eQTL data showed that 14 drug targets were significantly associated with ARHL. GO analysis of 14 potential targets revealed their primary involvement in biological processes such as the endoplasmic reticulum unfolded protein response, ER-nucleus signaling pathway, and fibroblast apoptotic process. Additionally, important cellular components include the Bcl-2 family of proteins and the endoplasmic reticulum lumen. After filtering using methods such as phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking, six potentially druggable genes (BAK1, AMFR, LAMP3, STK17B, ACP5, and CD9) and six drugs (beclomethasone, propyl pyrazole triol, momelotinib, monoisoamyl-2,3-dimercaptosuccinate, pterostilbene, and naftidrofuryl) that may affect ARHL outcomes were finally identified.

Conclusions: Our findings identified 14 potential drug targets for ARHL. These findings offer promising leads for more effective treatments for ARHL and help determine the priority of drug development, potentially reducing costs.