Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn’s disease

Abstract

BackgroundTo 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. AimWe 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. MethodsA 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. ResultsFailure 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). ConclusionsSNPs 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.