Genetically determined levels of mTOR-dependent circulating proteins and risk of multiple sclerosis

Abstract

Background Observational studies have reported an association between circulating levels of mammalian target of rapamycin (mTOR)-dependent circulating proteins and multiple sclerosis (MS). However, the casual association has not been fully elucidated. Mendelian randomization (MR) is used to overcome limitations inherent to observational studies and assess the causal association. Methods To explore the causal association between mTOR-dependent proteins (AKT, RP-S6K, eIF4E-BP, eIF4A, eIF4E, eIF4G, and PKC-α) and MS, summary statistics were obtained from GWAS meta-analysis of the International Multiple Sclerosis Genetics Consortium (47429 patients and 68374 controls) and the INTERVAL study (genetic associations with 2994 plasma proteins from 3301 healthy individuals). MR analysis and sensitivity analyses were conducted. Results Among seven selected mTOR-dependent proteins, the circulating level of PKC-α (OR = 0.90, 95%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, while no significant causation was found between other proteins (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. They might be used as future therapeutic targets for screening high-risk individuals.