Identification of Infliximab Responsiveness in Patients with Inflammatory Bowel Diseases using Whole-Exome Sequencing

抄録

Inflammatory bowel diseases (IBD) are chronic intesinal inflammatory disorders, Infliximab (IFX), an anti-TNF-alpha agent has been prescribed for the treatment of IBD. However, The response rates to IFX are different among patients, In this study, we investigated to identify genetic and clinical markers predictive of response to IFX. A total of 139 Korean patients with IBD who received IFX were classified according to IFX response; 1) primary response vs. non-response and 2) sustained response vs. loss of response. Then, we performed an association study using the whole exome sequencing data to find out genetic variants associated with response to IFX. Step-wise multivariate logistic regression was performed to find out predictors. We found that 6 representative SNPs were associated with non-response to IFX (P < 5 x 10^-6). In addition, we identified the best SNP (rs9144, P = 4.60 x 10^-6) associated with loss of response to IFX. In multivariate regression analysis with representative SNPs and clinical variables, chr2:114647924 (P = 8.08 x 10^-4; OR = 102.400), rs2289185 (P = 6.30 x 10^-4; OR = 18.910), rs2228273 (P = 0.004; OR = 22.060), male, concurrent azathioprine/6-mercaptopurine use, and body weight at the first IFX use (<50 kg) were associated with primary non-response. Additionally, Crohn's disease activity index at the first IFX use and rs9144 (P = 0.001; OR = 3.937) were independently associated with loss of response in CD patients. Our results support that the clinical and genetic predictors could expect the outcome of infliximab therapy in IBD patients. Although further study is required to explore the mechanistic functions of the genetic predictors, our findings could provide insights into maximizing efficacy for IBD patients with IFX therapy.