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Infliximab (IFX) is a chimeric anti-tumor necrosis factor-α monoclonal antibody exerting the therapeutic effect for Crohn’s disease (CD). To identify certain genes related to the effect of IFX and biomarkers to predict the effect of IFX, we examined an association study between 35 tag single nucleotide polymorphisms (SNPs) in six candidate genes involved in the P2RX7 signaling pathway and response to IFX after 10 weeks, 1 year, and 2 years of treatment for Japanese CD patients. A total of 127 CD patients were divided into two groups, including responders and non-responders, at each period of IFX treatment. The frequencies of alleles and genotyped at each tag SNP between responders and non-responders were compared in three different inheritance models at each period of treatment. Statistical analyses indicated that polymorphism of rs11670259 in CARD8 contributed to response and primary non-response to IFX after 10 weeks of treatment, and that polymorphisms of P2RX7, CARD8, and CASP1 independently contributed to response and secondary loss of response to IFX after 1 year of treatment. Subsequently, using the associated tag SNPs as a biomarker, genetic test revealed that the polymorphism of CARD8 and the combination polymorphisms of P2RX7 and CASP1 were useful as a biomarker to predict response to IFX after 10 weeks and 1 year of treatment, respectively. Therefore, CARD8 is an IFX-related gene after 10 weeks of treatment, and P2RX7, CARD8, and CASP1 are IFX-related genes after 1 year of treatment for Japanese CD patients. These genes in the P2RX7 signaling pathway could therefore be potential targets for new therapeutic drugs to combat primary non-response and secondary loss of response to IFX for CD patients. Abbreviations: ASC: apoptosis-associated speck-like protein containing a card; ATI: antibodies to IFX; CARD8: caspase recruitment domain-containing protein 8; CASP1: caspase 1; CD: Crohn’s disease; CDAI: Crohn’s disease activity index; HWE: Hardy-Weinberg equilibrium; IFX: infliximab; IL: interleukin; NF-κB: nuclear factor kappa-B; NLRP3: NLR family pyrin domain-containing 3; P2RX7: purinergic receptor P2X, ligand-gated ion channel, 7; SNPs: single nucleotide polymorphisms; TNF-α anti-tumor necrosis factor-alpha; TNFR: TNF receptor

integrative molecular medicine

The evidence of genetic polymorphisms of genes involved in the P2RX7 signaling pathway as predictive biomarkers for response and loss of response to infliximab against Crohn's disease