An analysis of data from the International Multiple Sclerosis Genetics Consortium identified five proteins that could be targets of future drug therapies for managing progressive multiple sclerosis.
Multiple sclerosis (MS) is a prevalent chronic neurological disease affecting young adults, characterized by inflammatory attacks followed by progressive disability. While current therapies primarily target inflammation and relapsing forms of MS, treatment for progressive MS (PMS) remains inadequate. Mendelian randomization (MR), integrating genome-wide association and protein quantitative trait loci (pQTL) data, offers a method to identify potential therapeutic targets. However, few MR studies have been conducted on MS.
This study identified plasma and cerebrospinal fluid (CSF) proteins as therapeutic targets for MS using MR analysis. Primary findings were validated using reverse causality detection, Bayesian co-localization analysis, and phenotype scanning. The results of the study were published in the journal Brain.
The Study Identified Five Proteins Affecting MS Progress
The study mainly used data from the International Multiple Sclerosis Genetics Consortium (nCase = 47,429, nControl = 68,374), further supported by data from the UK Biobank and FinnGen cohorts. The study identified 734 plasma and 154 CSF proteins from these datasets. Ultimately, six proteins that play a role in MS were identified. It was found that in plasma, per standard deviation increase in the following three proteins had a protective role: FCRL3 (odds ratio (OR) 0.83 (95% confidence interval (CI), 0.79–0.89)), TYMP (OR 0.59 (95% CI, 0.48–0.71)), and AHSG (OR 0.88 (95% CI, 0.83–0.94)).
With regard to CSF proteins, it was found that a 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42–7.41) increased MS risk, whereas SLAMF7 (OR, 0.42; 95% CI, 0.29–0.60) and CD5L (OR, 0.30; 95% CI, 0.18–0.52) decreased the risk. However, none of these proteins had reverse causality. Thus, the study concluded that five of these proteins, three in plasma (FCRL3, TYMP, and AHSG) and two in CSF (MMEL1 and SLAMF7), had a significant impact on multiple sclerosis risk.
The Bottom Line
This first-of-its-kind study identified five proteins that might be promising drug targets for MS. Particularly notable is the role of MMEL1, which was also confirmed by analysis of the UK Biobank and FinnGen cohorts. The other proteins of potential interest are FCRL3, TYMP, and SLAMF7. However, researchers think that the role of AHSG requires further study.
Notably, out of all five proteins identified in the study, previous studies have also suggested the role of three of these proteins: FCRL3, TYMP, and MMEL1. The study had some limitations, such as measurement inconsistencies among various studies. Further, more studies are needed on people of non-European ancestry. Nonetheless, the study could identify five proteins, in particular FCRL3 and SLAMF7, that could be targets of future drug therapies.
Source:
Lin, J., Zhou, J., & Xu, Y. (2023). Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis. Brain, 146(8), 3364–3372. https://doi.org/10.1093/brain/awad070
