DOP55 ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases using whole-exome sequencing. (25th January 2019)

• Record Type: Journal Article
• Authors: Jung, E S; Choi, K-w; Kim, S W; Hübenthal, M; Mucha, S; Park, J; Park, Z; Ellinghaus, D; Schreiber, S; Franke, A; Oh, W Y; Cheon, J H
• Is Part Of: Journal of Crohn's and colitis. Volume 13(2019)Supplement 1
• Page Start: S062
• Page End: S063
• Publication Date: 2019-01-25
• Subjects: Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjy222.089
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Thirteen per cent to 30% patients do not respond to the initial treatment, and 23%–46% patients who initially respond to IFX ultimately experience loss of response with time. 1–4 Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. Methods: One hundred and thirty-nine Korean patients with IBD who were treated by infliximab were classified according to infliximab response as follows: (1) primary response vs. non-response and (2) sustained response vs. loss of response. We conducted an association study using whole-exome sequencing data to identify genetic variants associated with infliximab response. Candidate variants were validated in 77 German patients with IBD. Stepwise multi-variate logistic regression was performed to identify predictors. Results: We found five candidate variants which were associated with primary non-response to infliximab ( p < 5 × 10 −6 ). Association mapping of genetic variants with primary non-response to infliximab in Korean patients with inflammatory bowel disease. Genetic variants related with primary non-response were plotted according to their chromosomal position. Of the five variants, rs2228273 in ZNF133 was validated in German patients (Combined p = 6.49 × 10 −7 ). We also identified the best genetic variant (rs9144, p = 4.60 × 10 −6 ) associated with loss of infliximab response. In multi-variate regression analysis, rs2228273 ( p = 2.10 × 10 −5 ), concurrent azathioprine/6-mercaptopurine use, and body weight at the first infliximab use (<50 kg) were associated with primary non-response. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 ( p = 0.001) were independently associated with loss of response in patients with Crohn's disease. Conclusions: We identified clinical and genetic markers associated with infliximab response in patients with IBD. Our findings could provide insights to maximise the efficacy of infliximab therapy in IBD. References 1. Sprakes MB, Ford AC, Warren L, et al. Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn's disease: a large single centre experience. J Crohns Colitis 2012;6:143–53. 2. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the accent I randomised trial. Lancet 2002;359:1541–9. 3. Ford AC, Sandborn WJ, Khan KJ, et al . Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2011;106:644–59. 4. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn's disease. Aliment Pharmacol Ther 2011;33:987–95.