Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis: a genome-wide multi-centric association study.
GRB2
LRP6
Multiple sclerosis
Natalizumab
Pharmacogenomics
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
12 Sep 2024
12 Sep 2024
Historique:
received:
15
04
2024
accepted:
23
07
2024
revised:
22
07
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
12
9
2024
Statut:
aheadofprint
Résumé
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. 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. 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 rs11132400 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.
Sections du résumé
BACKGROUND
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
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
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 rs11132400
CONCLUSION
CONCLUSIONS
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.
Identifiants
pubmed: 39264442
doi: 10.1007/s00415-024-12608-6
pii: 10.1007/s00415-024-12608-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Organisme : Horizon 2020 Framework Programme
ID : MultipleMS
Organisme : Horizon 2020 Framework Programme
ID : ID:733161
Informations de copyright
© 2024. The Author(s).
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