Eun Suk Jung1,2, Ko-Woon Choi3, Seung Won Kim1,4,5, Matthias Hübenthal2, Sören Mucha2, Jihye Park1, Zewon Park3, David Ellinghaus2, Stefan Schreiber2, Andre Franke2, Woo Yong Oh3, Jae Hee Cheon1,4,5. 1. Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. 2. Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany. 3. Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea. 4. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. 5. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Abstract
BACKGROUND AND AIM: Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. METHODS: A total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed 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 multivariate logistic regression was performed to identify predictors. RESULTS: We found five candidate variants that were associated with primary nonresponse to infliximab (P < 5 × 10-6 ). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P = 6.49 × 10-7 ). We also identified the best genetic variant (rs9144, P = 4.60 × 10-6 ) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P = 2.10 × 10-5 ), concurrent azathioprine/6-mercaptopurine use, and bodyweight at the first infliximab use (< 50 kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P = 0.001) were independently associated with the loss of response in patients with Crohn's disease. CONCLUSIONS: We identified clinical and genetic markers associated with infliximab response in IBD patients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBD patients.
BACKGROUND AND AIM: Infliximab has been widely prescribed for treating inflammatory bowel disease (IBD). However, the response rates to infliximab differ among patients. Therefore, we aimed to identify the genetic and clinical markers that predict infliximab response. METHODS: A total of 139 Korean patients with IBD who received infliximab were classified according to infliximab response as follows: (i) primary response vs nonresponse and (ii) sustained response vs loss of response. We performed 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 multivariate logistic regression was performed to identify predictors. RESULTS: We found five candidate variants that were associated with primary nonresponse to infliximab (P < 5 × 10-6 ). Of the five variants, rs2228273 in ZNF133 was validated in German (combined P = 6.49 × 10-7 ). We also identified the best genetic variant (rs9144, P = 4.60 × 10-6 ) associated with the loss of infliximab response. In multivariate regression analysis, rs2228273 (P = 2.10 × 10-5 ), concurrent azathioprine/6-mercaptopurine use, and bodyweight at the first infliximab use (< 50 kg) were associated with primary nonresponse. In addition, the Crohn's disease activity index at the first infliximab use and rs9144 (P = 0.001) were independently associated with the loss of response in patients with Crohn's disease. CONCLUSIONS: We identified clinical and genetic markers associated with infliximab response in IBDpatients. Our findings could provide insights to maximize the efficacy of infliximab therapy in IBDpatients.