Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn’s disease - 03/02/23
, S. Salvador-Martín e, f, 1, A. Arias c, d, g, B. López-Cauce f, h, I. Marín-Jiménez f, h, L.A. Menchén f, h, L. Marín-Rubio i, J. Ontañón Rodríguez i, L.A. López-Fernández e, f, 2, A.J. Lucendo a, c, d, j, ⁎, 2 Abstract |
Background |
To predict primary failure of infliximab (IFX) therapy in Crohn’s disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers.
Aim |
We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients.
Methods |
A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed.
Results |
Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1–0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1–0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1–7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22–0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27–0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544).
Conclusions |
SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Biomarkers to predict response to IFX in Crohn's disease are lacking. |
• | After analyzing sixty-six SNPs and HLADQA1*05, three SNPs in ADAM17, IL23R and SLCO1C1 genes were identified to protect against IFX failure. |
• | When these SNPs were not present, concomitant immunosuppressant is highly advisable. |
• | Absence of bowel resection also contributed to IFX persistence. |
Keywords : Crohn’s disease, Infliximab, Long-term response, Pharmacogenomics, Single nucleotide polymorphisms
Abbreviations : CD, CI, HRa, IBD, IQR, IFX, ORa, NF-kβ, SNP, SSO, TDM, TNFα
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Vol 159
Article 114225- mars 2023 Retour au numéro
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