Response to Infliximab in Crohn’s Disease: Genetic Analysis Supporting Expression Profile

Abstract

Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276*G/rs3014866*C/rs724781*C/rs3006488*A; P = 0.05); G0S2 (rs4844486*A/rs1473683*T; P = 0.15); TNFAIP6 (rs11677200*C/rs2342910*A/rs3755480*G/rs10432475*A; P = 0.10); and IL11 (rs1126760*C/rs1042506*G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

Genetic prediction profile for adalimumab response in Slovenian Crohn’s disease patients

“…In addition, we performed SVM analysis of selected SNPs from analyzed genes. These SNPs and haplotype frequencies were previously associated with response to IFX treatment [12]. Using genotypes from selected SNPs or their high LD mates, we were able to obtain an average of 92.8 % accurate prediction of ADA response, confirming the involvement of genetic regions mapping the reported genes.…”

“…It was previously reported that an expression profile of 5 epithelial genes (TNFAIP6, S100A8, S100A9, IL11, and G0S2) predicts a signature for response or non-response to IFX in refractory patients with Crohn's colitis with an accuracy of 100 %, but no prediction expression profile could be identified for Crohn's ileitis [11]. This reported predictive signature expression profile to IFX is also supported by independent Spanish cohort genetic analysis that suggests association of SNPs and haplotypes in aforementioned 5 genes with IFX response [12]. Although IFX and ADA target the same principal inflammatory cytokine (TNF-α), IFX is a chimeric mouse/human monoclonal antibody, whereas ADA is fully humanized.…”

“…Single nucleotide polymorphisms were selected from haplotype blocks reported by Medrano et al [12] and based on previously reported genes TNFAIP6, S100A8, S100A9, and G0S2 [11]. DNA for genotyping was extracted from peripheral blood mononuclear cells using TRI reagent (Merck) according to the manufacturer's instructions.…”

New Biomarkers for Diagnosing Inflammatory Bowel Disease and Assessing Treatment Outcomes

“…139,140 Gene expression analysis offers a particularly attractive tool, as it could be performed prior to initiation of therapy and thus offers a prediction of response prior to use of a therapy that may ultimately provide a less than desirable treatment effect. Techniques utilizing analysis of “metagenes,” transcript sets that have been derived to reflect ongoing biologic change within a mucosal biopsy, have also demonstrated utility in the identification of predictors of the response to IFX therapy among patients with UC.…”

Pharmacogenetic biomarkers of response in Crohn’s disease

“…The influence of rs116760 and rs1042506 polymorphisms in IL11 gene on response to IFX were investigated in 350 patients (Table 3) (66). Response criteria were established as HBI<4 for luminal CD and 100% fistulae healing for fistulising CD patients; partial responders were defined as HBI<3 and >50% reduction in fistulae, respectively.…”