ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases
Eun Suk Jung
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
E.S. Jung and K. Choi contributed equally to this study.Search for more papers by this authorKo-woon Choi
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea
E.S. Jung and K. Choi contributed equally to this study.Search for more papers by this authorSeung Won Kim
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Search for more papers by this authorMatthias Hübenthal
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorSören Mucha
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorJihye Park
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Search for more papers by this authorZewon Park
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea
Search for more papers by this authorDavid Ellinghaus
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorStefan Schreiber
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorAndre Franke
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorCorresponding Author
Woo Yong Oh
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea
Correspondence
Dr Jae Hee Cheon, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Email: [email protected]
Woo Yong Oh, Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju 28159, Korea.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jae Hee Cheon
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Correspondence
Dr Jae Hee Cheon, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Email: [email protected]
Woo Yong Oh, Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju 28159, Korea.
Email: [email protected]
Search for more papers by this authorEun Suk Jung
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
E.S. Jung and K. Choi contributed equally to this study.Search for more papers by this authorKo-woon Choi
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea
E.S. Jung and K. Choi contributed equally to this study.Search for more papers by this authorSeung Won Kim
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Search for more papers by this authorMatthias Hübenthal
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorSören Mucha
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorJihye Park
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Search for more papers by this authorZewon Park
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea
Search for more papers by this authorDavid Ellinghaus
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorStefan Schreiber
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorAndre Franke
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Search for more papers by this authorCorresponding Author
Woo Yong Oh
Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju, Korea
Correspondence
Dr Jae Hee Cheon, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Email: [email protected]
Woo Yong Oh, Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju 28159, Korea.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jae Hee Cheon
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Correspondence
Dr Jae Hee Cheon, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Email: [email protected]
Woo Yong Oh, Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Cheongju 28159, Korea.
Email: [email protected]
Search for more papers by this authorAbstract
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.
Supporting Information
| Filename | Description |
|---|---|
| jgh14652-sup-0001-TableS1.docxWord 2007 document , 18.3 KB |
Table S1. Clinical characteristics of all patients (N = 135). |
| jgh14652-sup-0002-TableS2.docxWord 2007 document , 17.1 KB |
Table S2. Comparison of the characteristics of 104 patients with CD and 31 patients with UC (primary responders vs. nonresponders to infliximab). |
| jgh14652-sup-0003-TableS3.docxWord 2007 document , 16.6 KB |
Table S3. In silico prediction for protein function of variants in response to infliximab therapy in patients with inflammatory bowel disease. |
| jgh14652-sup-0004-TableS4.docxWord 2007 document , 15.2 KB |
Table S4. Gene-based test (Variable threshold) of ZNF133 in comparison between primary responder and primary non-responder. |
| jgh14652-sup-0005-TableS5.docxWord 2007 document , 13 KB |
Table S5. Predictive models of primary nonresponse to infliximab. |
| jgh14652-sup-0006-TableS6.docxWord 2007 document , 17.3 KB |
Table S6. Comparison of the characteristics of 77 patients with CD and 27 patients with UC (those with sustained response vs. those with lost response to infliximab). |
| jgh14652-sup-0007-TableS7.docxWord 2007 document , 14.1 KB |
Table S7. Predictive models of loss of response to infliximab. |
| jgh14652-sup-0008-FigureS1.tifTIFF image, 382.5 KB |
Figure S1. Study Scheme. |
| jgh14652-sup-0009-FigureS2.tifTIFF image, 1.5 MB |
Figure S2. Association mapping of genetic variants with primary nonresponse to infliximab in Korean patients with inflammatory bowel disease. |
| jgh14652-sup-0010-FigureS3.tifTIFF image, 748.9 KB |
Figure S3. Results of linkage disequilibrium (D′=1.0 and r2=1.0) between the rs34099160 and rs2228273. |
| jgh14652-sup-0011-FigureS4.tifTIFF image, 1.4 MB |
Figure S4. Association mapping of genetic variants with loss of response to infliximab in Korean patients with inflammatory bowel disease. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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