Pharmacogenomics of response to interferon-beta and glatiramer acetate in Multiple Sclerosis: A multi-centric study

Background: Multiple sclerosis (MS) treatment response varies significantly, hindering effective management and necessitating better predictive biomarkers. Pharmacogenomics offers a promising avenue to identify genetic markers that, combined with clinico-demographic predictors, could enhance personalized therapeutic decisions. Objectives: This multi-center study investigated genetic determinants of response to interferon-beta (IFN-β) and glatiramer acetate (GA) in European ancestry patients with relapsing–remitting MS (RRMS). Methods: After harmonization and quality control, we tested over 6 million genetic variants. We used negative binomial regression, meta-analysis, and gene-set enrichment to link variants, genes, and biological pathways to treatment response. Results: In 679 GA and 1614 IFN-β patients, the top GA variant was rs2053696A in MAP3 K1 (p = 3.97*10−9), involved in key signaling pathways. Another significant GA signal was in WWOX. For IFN-β, no genome-wide significant variants were found, but suggestive signals emerged near ZMIZ1, ZCCHC7, and other genes linked to immune function and interferon signaling. Gene-set analysis revealed IL-17 regulation for GA and ion channel pathways for IFN-β. Conclusion: This study identified novel genetic variants for GA response, implicating genes in crucial pathways. For IFN-β, suggestive signals point to immune and interferon-related genes. These findings enhance our understanding of genetic influences on RRMS treatment response, while highlighting pharmacogenomic research challenges.