Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis

Clarelli, Ferdinando; Corona, Andrea; Pääkkönen, Kimmo; Sorosina, Melissa; Zollo, Alen; Piehl, Fredrik; Olsson, Tomas; Stridh, Pernilla; Jagodic, Maja; Hemmer, Bernhard ; Gasperi, Christiane; Harroud, Adil; Shchetynsky, Klementy; Mingione, Alessandra; Mascia, Elisabetta; Misra, Kaalindi; Giordano, Antonino; Mazzieri, Maria Laura Terzi; Priori, Alberto; Saarela, Janna; Kockum, Ingrid; Filippi, Massimo; Esposito, Federica und Boneschi, Filippo Giovanni Martinelli (2024): Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis. A genome-wide multi-centric association study. In: Journal of Neurology, Bd. 271, Nr. 11: S. 7250-7263

Abstract

Background : Inter-individual differences in treatment response are marked in multiple sclerosis (MS). This is true for Natalizumab (NTZ), to which a subset of patients displays sub-optimal treatment response. We conducted a multi-centric genome-wide association study (GWAS), with additional pathway and network analysis to identify genetic predictors of response to NTZ. Methods : MS patients from three different centers were included. Response to NTZ was dichotomized, nominating responders (R) relapse-free patients and non-responders (NR) all the others, over a follow-up of 4 years. Association analysis on ~ 4.7 M imputed autosomal common single-nucleotide polymorphisms (SNPs) was performed fitting logistic regression models, adjusted for baseline covariates, followed by meta-analysis at SNP and gene level. Finally, these signals were projected onto STRING interactome, to elicit modules and hub genes linked to response. Results : Overall, 1834 patients were included: 119 from Italy (R = 94, NR = 25), 81 from Germany (R = 61, NR = 20), and 1634 from Sweden (R = 1349, NR = 285). The top-associated variant was rs11132400T (p = 1.33 × 10–6, OR = 0.58), affecting expression of several genes in the locus, like KLKB1. The interactome analysis implicated a module of 135 genes, with over-representation of terms like canonical WNT signaling pathway (padjust = 7.08 × 10–6). Response-associated genes like GRB2 and LRP6, already implicated in MS pathogenesis, were topologically prioritized within the module. Conclusion : This GWAS, the largest pharmacogenomic study of response to NTZ, suggested MS-implicated genes and Wnt/β-catenin signaling pathway, an essential component for blood–brain barrier formation and maintenance, to be related to treatment response.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0340-5354
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198