Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis
Abstract Background Results from observational studies indicate an association between circulating levels of mammalian target of rapamycin (mTOR)-dependent circulating proteins and the risk of multiple sclerosis (MS). However, a causal association has not been fully elucidated. Mendelian randomizati...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Adis, Springer Healthcare
2023-03-01
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| Series: | Neurology and Therapy |
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| Online Access: | https://doi.org/10.1007/s40120-023-00455-y |
| _version_ | 1797822606936637440 |
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| author | Yao-Chen Zhang Ke-Yi Fan Qi Wang Jing-Xi Hu Qian Wang He-Yi Zhang Shan Song Rong Zhao Jun Qiao Sheng-Xiao Zhang |
| author_facet | Yao-Chen Zhang Ke-Yi Fan Qi Wang Jing-Xi Hu Qian Wang He-Yi Zhang Shan Song Rong Zhao Jun Qiao Sheng-Xiao Zhang |
| author_sort | Yao-Chen Zhang |
| collection | DOAJ |
| description | Abstract Background Results from observational studies indicate an association between circulating levels of mammalian target of rapamycin (mTOR)-dependent circulating proteins and the risk of multiple sclerosis (MS). However, a causal association has not been fully elucidated. Mendelian randomization (MR) is used to overcome limitations inherent to observational studies, assess the causal association, and minimize bias due to confounding and reverse causation. Methods To explore the causal association between seven mTOR-dependent proteins (AKT, RP-S6K, eIF4E-BP, eIF4A, eIF4E, eIF4G, and PKC-α) and MS, we obtained summary statistics from the genome-wide association study (GWAS) meta-analysis of the International Multiple Sclerosis Genetics Consortium (47,429 patients and 68,374 controls) and the INTERVAL study (genetic associations with 2994 plasma proteins from 3301 healthy individuals). MR analyses were conducted using inverse variance weighted, weighted median estimator, and MR-Egger regression methods/models. Sensitivity analyses were performed to ensure the reliability of the findings. Single nucleotide polymorphisms (SNPs) that are independent (r 2 < 0.01) and strongly associated to minerals (p < 1e−5) were selected as instrumental variables. Results The results of the MR analyses revealed that among the seven mTOR-dependent proteins selected for study, the circulating level of PKC-α (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.82–0.98; P = 0.017) and RP-S6K (OR 1.12, 95% CI 1.00–1.25; P = 0.045) were associated with MS risk and that there was no sign of pleiotropy or heterogeneity. PKC-α was negatively related to MS, while RP-S6K was positively related to MS. No significant causation was found between the other proteins studied (AKT, eIF4E-BP, eIF4A, eIF4E, eIF4G) and MS. Conclusion Molecules in the mTOR signaling pathway may bidirectionally regulate the occurrence and development of MS. PKC-α is a protective factor, while RP-S6K is a risk factor. Further explorations of pathways underlying the association between mTOR-dependent proteins and MS are required. PKC-α and RP-S6K might be used as future therapeutic targets for screening high-risk individuals and potentially improving opportunities for targeted prevention strategies. |
| first_indexed | 2024-03-13T10:11:36Z |
| format | Article |
| id | doaj.art-7571dd8b03eb45288d12d19f2f215478 |
| institution | Directory Open Access Journal |
| issn | 2193-8253 2193-6536 |
| language | English |
| last_indexed | 2024-03-13T10:11:36Z |
| publishDate | 2023-03-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Neurology and Therapy |
| spelling | doaj.art-7571dd8b03eb45288d12d19f2f2154782023-05-21T11:30:43ZengAdis, Springer HealthcareNeurology and Therapy2193-82532193-65362023-03-0112375176210.1007/s40120-023-00455-yGenetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple SclerosisYao-Chen Zhang0Ke-Yi Fan1Qi Wang2Jing-Xi Hu3Qian Wang4He-Yi Zhang5Shan Song6Rong Zhao7Jun Qiao8Sheng-Xiao Zhang9Department of Rheumatology, The Second Hospital of Shanxi Medical UniversityShanxi Provincial Key Laboratory of Rheumatism Immune MicroecologyKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of EducationShanxi Provincial Key Laboratory of Rheumatism Immune MicroecologyShanxi Provincial Key Laboratory of Rheumatism Immune MicroecologyShanxi Provincial Key Laboratory of Rheumatism Immune MicroecologyDepartment of Rheumatology, The Second Hospital of Shanxi Medical UniversityDepartment of Rheumatology, The Second Hospital of Shanxi Medical UniversityDepartment of Rheumatology, The Second Hospital of Shanxi Medical UniversityDepartment of Rheumatology, The Second Hospital of Shanxi Medical UniversityAbstract Background Results from observational studies indicate an association between circulating levels of mammalian target of rapamycin (mTOR)-dependent circulating proteins and the risk of multiple sclerosis (MS). However, a causal association has not been fully elucidated. Mendelian randomization (MR) is used to overcome limitations inherent to observational studies, assess the causal association, and minimize bias due to confounding and reverse causation. Methods To explore the causal association between seven mTOR-dependent proteins (AKT, RP-S6K, eIF4E-BP, eIF4A, eIF4E, eIF4G, and PKC-α) and MS, we obtained summary statistics from the genome-wide association study (GWAS) meta-analysis of the International Multiple Sclerosis Genetics Consortium (47,429 patients and 68,374 controls) and the INTERVAL study (genetic associations with 2994 plasma proteins from 3301 healthy individuals). MR analyses were conducted using inverse variance weighted, weighted median estimator, and MR-Egger regression methods/models. Sensitivity analyses were performed to ensure the reliability of the findings. Single nucleotide polymorphisms (SNPs) that are independent (r 2 < 0.01) and strongly associated to minerals (p < 1e−5) were selected as instrumental variables. Results The results of the MR analyses revealed that among the seven mTOR-dependent proteins selected for study, the circulating level of PKC-α (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.82–0.98; P = 0.017) and RP-S6K (OR 1.12, 95% CI 1.00–1.25; P = 0.045) were associated with MS risk and that there was no sign of pleiotropy or heterogeneity. PKC-α was negatively related to MS, while RP-S6K was positively related to MS. No significant causation was found between the other proteins studied (AKT, eIF4E-BP, eIF4A, eIF4E, eIF4G) and MS. Conclusion Molecules in the mTOR signaling pathway may bidirectionally regulate the occurrence and development of MS. PKC-α is a protective factor, while RP-S6K is a risk factor. Further explorations of pathways underlying the association between mTOR-dependent proteins and MS are required. PKC-α and RP-S6K might be used as future therapeutic targets for screening high-risk individuals and potentially improving opportunities for targeted prevention strategies.https://doi.org/10.1007/s40120-023-00455-yMultiple sclerosisMendelian randomization analysismTOR-associated proteinMolecular epidemiology |
| spellingShingle | Yao-Chen Zhang Ke-Yi Fan Qi Wang Jing-Xi Hu Qian Wang He-Yi Zhang Shan Song Rong Zhao Jun Qiao Sheng-Xiao Zhang Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis Neurology and Therapy Multiple sclerosis Mendelian randomization analysis mTOR-associated protein Molecular epidemiology |
| title | Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis |
| title_full | Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis |
| title_fullStr | Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis |
| title_full_unstemmed | Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis |
| title_short | Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis |
| title_sort | genetically determined levels of mtor dependent circulating proteins and risk of multiple sclerosis |
| topic | Multiple sclerosis Mendelian randomization analysis mTOR-associated protein Molecular epidemiology |
| url | https://doi.org/10.1007/s40120-023-00455-y |
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