Sang Hyoung Park1, Myunghee Hong2, Ho-Su Lee2, Byong Duk Ye1, Sung Wook Hwang1, Seulgi Jung2, Jiwon Baek2, Jung Won Moon2, Byoung Mok Kim2, Seak Hee Oh3, Kyung Mo Kim3, Inchul Lee4, Chang-Nim Im5, Jianjun Liu6, Dermot P B McGovern7, Suk-Kyun Yang1, Kyuyoung Song2. 1. Department of Gastroenterology, Asan Medical Center, Seoul, Korea. 2. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea. 3. Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, Korea. 4. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 5. Department of Biochemistry, Institute for Aging and Metabolic Diseases, Cancer Evolution Center, College of Medicine, The Catholic University of Korea, Seoul, Korea. 6. Human Genetics Group, Genome Institute of Singapore, Singapore. 7. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Abstract
BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX), have been increasingly used to induce and maintain disease remission in patients with Crohn's disease (CD). Despite a considerable non-response rate, little is known about the genetic predictors of response to anti-TNF therapy in CD. Our aim in this study was to investigate the genetic factors associated with response to anti-TNF therapy in patients with CD. METHODS: We performed a two-stage genome-wide association study (GWAS) to identify loci influencing the response to IFX among Korean patients with CD, comprising 42 good responders with mucosal healing and 70 non-responders. The achievement of mucosal healing was assessed by endoscopy and imaging. The functional significance of TRAP1 (TNF receptor associated protein 1) was examined using dextran sodium sulfate-induced colitis model in TRAP1 transgenic mice. RESULTS: The GWAS identified rs2158962, an intronic single nucleotide polymorphism (SNP) of TRAP1, significantly associated with mucosal healing (odds ratio = 4.94; Pcombined = 1.35 × 10-7 ). In the dextran sodium sulfate-induced acute colitis, TRAP1 transgenic mice showed a better response to IFX than the wild-type mice. CONCLUSIONS: The TRAP1 gene is associated with mucosal healing in CD patients following IFX therapy. Identifying the genetic predictors of mucosal healing to anti-TNF therapy can prevent patients from exposure to ineffective therapies.
BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) agents, such as infliximab (IFX), have been increasingly used to induce and maintain disease remission in patients with Crohn's disease (CD). Despite a considerable non-response rate, little is known about the genetic predictors of response to anti-TNF therapy in CD. Our aim in this study was to investigate the genetic factors associated with response to anti-TNF therapy in patients with CD. METHODS: We performed a two-stage genome-wide association study (GWAS) to identify loci influencing the response to IFX among Korean patients with CD, comprising 42 good responders with mucosal healing and 70 non-responders. The achievement of mucosal healing was assessed by endoscopy and imaging. The functional significance of TRAP1 (TNF receptor associated protein 1) was examined using dextran sodium sulfate-induced colitis model in TRAP1transgenic mice. RESULTS: The GWAS identified rs2158962, an intronic single nucleotide polymorphism (SNP) of TRAP1, significantly associated with mucosal healing (odds ratio = 4.94; Pcombined = 1.35 × 10-7 ). In the dextran sodium sulfate-induced acute colitis, TRAP1transgenic mice showed a better response to IFX than the wild-type mice. CONCLUSIONS: The TRAP1 gene is associated with mucosal healing in CDpatients following IFX therapy. Identifying the genetic predictors of mucosal healing to anti-TNF therapy can prevent patients from exposure to ineffective therapies.