Exploring the mediating role of cerebrospinal fluid metabolites in the pathway from circulating inflammatory proteins to multiple sclerosis: A Mendelian randomization study
Multiple Sclerosis and Related Disorders, 2025
Mao X., Lu X., Liu Y., Wu H., Li B., Bi X.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Neurology | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Background
Multiple sclerosis (MS) is an autoimmune disease in which inflammation plays a pivotal role in its pathogenesis. The inflammatory response is regulated by a complex network of cells and mediators, including circulating proteins such as cytokines and inflammatory mediators. Metabolomics is a powerful analytical approach that may provide diagnostic and therapeutic targets for MS. However, the causal effects of circulating inflammatory proteins and cerebrospinal fluid metabolites (CSFMs) on MS, as well as whether CSFMs act as mediators, remain unclear.
Objective
In this study, we obtained data on circulating inflammatory proteins, CSFMs, and MS from the largest genome-wide association study (GWAS) dataset of the International Multiple Sclerosis Genetics Consortium (IMSGC).
Methods
We utilized the Mendelian randomization (MR) mediation analysis method to investigate the causal relationships among circulating inflammatory proteins, CSFMs and MS. Inverse variance weighting (IVW) served as the primary statistical method. Additionally, we explored whether CSFMs act as mediators in the pathway from circulating inflammatory proteins to MS.
Results
Our findings reveal that there are five inflammatory proteins associated with MS. MR analysis reveals a positive correlation between the genetic prediction of three inflammatory proteins and the occurrence of MS. Our study reveals a link between 10 CSFMs and MS. Further MR analysis reveals a positive correlation between the genetic prediction of 6 CSFMs and the development of MS. Notably, CSFMs do not exhibit a reverse effect on MS. Our study establishes a significant causal effect of circulating inflammatory proteins and CSFMs on the progression of MS. Furthermore, CSFMs do not serve as an intermediary factor in the pathway connecting inflammatory proteins with MS. Circulating inflammatory proteins and CSFMs are causally associated with MS, and CSFMs do not appear to be intermediate factors in the pathway from inflammatory proteins to MS.