Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes
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 per...
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Elsevier
2025-02-01
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| Series: | Experimental Gerontology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S053155652500004X |
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| author | Kun Zhang Bo Hou Tao Yan Ruru Qiao Peng Qu Xinbo Xu Hanbing Zhang |
| author_facet | Kun Zhang Bo Hou Tao Yan Ruru Qiao Peng Qu Xinbo Xu Hanbing Zhang |
| author_sort | Kun Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c07a972edc5b4387b4b0920e98010f79 |
| institution | Kabale University |
| issn | 1873-6815 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Experimental Gerontology |
| spelling | doaj-art-c07a972edc5b4387b4b0920e98010f792025-01-31T05:10:07ZengElsevierExperimental Gerontology1873-68152025-02-01200112676Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genesKun Zhang0Bo Hou1Tao Yan2Ruru Qiao3Peng Qu4Xinbo Xu5Hanbing Zhang6Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, ChinaDepartment of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, ChinaDepartment of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, ChinaDepartment of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, ChinaHospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China; Correspondence to: P. Qu, Hospital for Skin Diseases, Shandong First Medical University, 27397 Jingshi Road of Jinan, Shandong, 250022, China.Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, China; Corresponding authors at: Department of Otorhinolaryngology, Qilu Hospital of Shandong University, 107 Wenhua West Road of Jinan, Shandong, 250012, China.Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, China; NHC Key Laboratory of Otorhinolaryngology, Shandong University, Jinan, Shandong, China; Corresponding authors at: Department of Otorhinolaryngology, Qilu Hospital of Shandong University, 107 Wenhua West Road of Jinan, Shandong, 250012, China.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.http://www.sciencedirect.com/science/article/pii/S053155652500004XARHLMendelian randomizationDruggable target genesColocalization analyses |
| spellingShingle | Kun Zhang Bo Hou Tao Yan Ruru Qiao Peng Qu Xinbo Xu Hanbing Zhang Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes Experimental Gerontology ARHL Mendelian randomization Druggable target genes Colocalization analyses |
| title | Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes |
| title_full | Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes |
| title_fullStr | Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes |
| title_full_unstemmed | Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes |
| title_short | Identification of therapeutic target genes for age-related hearing loss through systematic genome-wide mendelian randomization of druggable genes |
| title_sort | identification of therapeutic target genes for age related hearing loss through systematic genome wide mendelian randomization of druggable genes |
| topic | ARHL Mendelian randomization Druggable target genes Colocalization analyses |
| url | http://www.sciencedirect.com/science/article/pii/S053155652500004X |
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