Genetically Determined Levels of mTOR-Dependent Circulating Proteins and Risk of Multiple Sclerosis

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40120-023-00455-y.