Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets
Background Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integr...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | BMC Genomics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12864-024-10116-5 |
| _version_ | 1797275764902592512 |
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| author | Kaixi Ding Juejue Zhangwang Ming Lei Chunping Xiong |
| author_facet | Kaixi Ding Juejue Zhangwang Ming Lei Chunping Xiong |
| author_sort | Kaixi Ding |
| collection | DOAJ |
| description | Background Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. Methods Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. Results After Bonferron correction (p < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). Conclusion Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed. |
| first_indexed | 2024-03-07T15:19:06Z |
| format | Article |
| id | doaj.art-8a5ec836a64444568ae4ae41ebf3c0fa |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-03-07T15:19:06Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-8a5ec836a64444568ae4ae41ebf3c0fa2024-03-05T17:46:20ZengBMCBMC Genomics1471-21642024-03-0125111510.1186/s12864-024-10116-5Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targetsKaixi Ding0Juejue Zhangwang1Ming Lei2Chunping Xiong3School of Clinical Medicine, Chengdu University of Traditional Chinese MedicineSchool of Clinical Medicine, Chengdu University of Traditional Chinese MedicineHospital of Chengdu University of Traditional Chinese MedicineHospital of Chengdu University of Traditional Chinese MedicineBackground Telomere length is a critical metric linked to aging, health, and disease. Currently, the exploration of target proteins related to telomere length is usually limited to the context of aging and specific diseases, which limits the discovery of more relevant drug targets. This study integrated large-scale plasma cis-pQTLs data and telomere length GWAS datasets. We used Mendelian randomization(MR) to identify drug target proteins for telomere length, providing essential clues for future precision therapy and targeted drug development. Methods Using plasma cis-pQTLs data from a previous GWAS study (3,606 Pqtls associated with 2,656 proteins) and a GWAS dataset of telomere length (sample size: 472,174; GWAS ID: ieu-b-4879) from UK Biobank, using MR, external validation, and reverse causality testing, we identified essential drug target proteins for telomere length. We also performed co-localization, Phenome-wide association studies and enrichment analysis, protein-protein interaction network construction, search for existing intervening drugs, and potential drug/compound prediction for these critical targets to strengthen and expand our findings. Results After Bonferron correction (p < 0.05/734), RPN1 (OR: 0.96; 95%CI: (0.95, 0.97)), GDI2 (OR: 0.94; 95%CI: (0.92, 0.96)), NT5C (OR: 0.97; 95%CI: (0.95, 0.98)) had a significant negative causal association with telomere length; TYRO3 (OR: 1.11; 95%CI: (1.09, 1.15)) had a significant positive causal association with telomere length. GDI2 shared the same genetic variants with telomere length (coloc.abf-PPH 4 > 0.8). Conclusion Genetically determined plasma RPN1, GDI2, NT5C, and TYRO3 have significant causal effects on telomere length and can potentially be drug targets. Further exploration of the role and mechanism of these proteins/genes in regulating telomere length is needed.https://doi.org/10.1186/s12864-024-10116-5Telomere lengthProtein expression regulatory lociMendelian randomizationTarget proteinsCausal associations |
| spellingShingle | Kaixi Ding Juejue Zhangwang Ming Lei Chunping Xiong Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets BMC Genomics Telomere length Protein expression regulatory loci Mendelian randomization Target proteins Causal associations |
| title | Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets |
| title_full | Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets |
| title_fullStr | Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets |
| title_full_unstemmed | Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets |
| title_short | Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets |
| title_sort | insight into telomere regulation road to discovery and intervention in plasma drug protein targets |
| topic | Telomere length Protein expression regulatory loci Mendelian randomization Target proteins Causal associations |
| url | https://doi.org/10.1186/s12864-024-10116-5 |
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