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.

Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis: a genome-wide multi-centric association study / Clarelli, F.; Corona, A.; Paakkonen, K.; Sorosina, M.; Zollo, A.; Piehl, F.; Olsson, T.; Stridh, P.; Jagodic, M.; Hemmer, B.; Gasperi, C.; Harroud, A.; Shchetynsky, K.; Mingione, A.; Mascia, E.; Misra, K.; Giordano, A.; Mazzieri, M. L. T.; Priori, A.; Saarela, J.; Kockum, I.; Filippi, M.; Esposito, F.; Boneschi, F. G. M.. - In: JOURNAL OF NEUROLOGY. - ISSN 0340-5354. - 271:11(2024), pp. 7250-7263. [10.1007/s00415-024-12608-6]

Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis: a genome-wide multi-centric association study

Mascia E.;Misra K.;Giordano A.;Filippi M.;
2024-01-01

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.
2024
GRB2
LRP6
Multiple sclerosis
Natalizumab
Pharmacogenomics
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/169697
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