Multiple sclerosis (Houndmills, Basingstoke, England) · 2026
Pharmacogenomics of response to interferon-beta and glatiramer acetate in Multiple Sclerosis: A multi-centric study.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Corona Andrea, Clarelli Ferdinando, Pääkkönen Kimmo, Harroud Adil, Shchetynsky Klementy, Zollo Alen, Mingione Alessandra, Sorosina Melissa, Mascia Elisabetta, Giordano Antonino, Rocca Maria Assunta, Piehl Fredrik, Stridh Pernilla, Hemmer Bernhard, Goris An, Dubois Bénédicte, Søndergaard Helle Bach, Sellebjerg Finn, D'alfonso Sandra, Harbo Hanne Flinstad, Olsson Tomas, Saarela Janna, Priori Alberto, Filippi Massimo, Kockum Ingrid, Esposito Federica, Martinelli Boneschi Filippo
Аннотация
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.
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.