Han Sang Kim1,2, Jae Hee Cheon2,3, Eun Suk Jung1,3, Joonhee Park1, Sowon Aum1, Soo Jung Park3, Sungho Eun1, Jinu Lee4, Ulrich Rüther5, Giles S H Yeo6, Marcella Ma6, Kyong Soo Park7, Takeo Naito8, Yoichi Kakuta8, Ji Hyun Lee9, Won Ho Kim3, Min Goo Lee1,2. 1. Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. 2. Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. 3. Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. 4. College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Inchon, Korea. 5. Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Universitätsstr. 1, Düsseldorf, Germany. 6. University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. 7. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. 8. Division of Gastroenterology, Tohoku University Hospital, Miyagi, Japan. 9. Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Korea.
Abstract
OBJECTIVE: Myelosuppression is a life-threatening complication of thiopurine therapy, and the incidence of thiopurine-induced myelosuppression is higher in East Asians than in Europeans. We investigated genetic factors associated with thiopurine-induced leukopenia in patients with IBD. DESIGN: A genome-wide association study (GWAS) was conducted in thiopurine-treated patients with IBD, followed by high-throughput sequencing of genes identified as significant in the GWAS or those involved in thiopurine metabolism (n=331). Significant loci associated with thiopurine-induced leukopenia were validated in two additional replication cohorts (n=437 and n=330). Functional consequences of FTO (fat mass and obesity-associated) variant were examined both in vitro and in vivo. RESULTS: The GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920, FTO intron; rs2834826, RUNX1 intergenic). High-throughput targeted sequencing indicated that an FTO coding variant (rs79206939, p.A134T) linked to rs16957920 is associated with thiopurine-induced leukopenia. This result was further validated in two replication cohorts (combined p=1.3×10-8, OR=4.3). The frequency of FTO p.A134T is 5.1% in Koreans but less than 0.1% in Western populations. The p.A134T variation reduced FTO activity by 65% in the nucleotide demethylase assay. In vivo experiments revealed that Fto-/- and Fto+/- mice were more susceptible to thiopurine-induced myelosuppression than wild-type mice. CONCLUSIONS: The results suggest that the hypomorphic FTO p.A134T variant is associated with thiopurine-induced leukopenia. These results shed light on the novel physiological role of FTO and provide a potential pharmacogenetic biomarker for thiopurine therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
OBJECTIVE:Myelosuppression is a life-threatening complication of thiopurine therapy, and the incidence of thiopurine-induced myelosuppression is higher in East Asians than in Europeans. We investigated genetic factors associated with thiopurine-induced leukopenia in patients with IBD. DESIGN: A genome-wide association study (GWAS) was conducted in thiopurine-treated patients with IBD, followed by high-throughput sequencing of genes identified as significant in the GWAS or those involved in thiopurine metabolism (n=331). Significant loci associated with thiopurine-induced leukopenia were validated in two additional replication cohorts (n=437 and n=330). Functional consequences of FTO (fat mass and obesity-associated) variant were examined both in vitro and in vivo. RESULTS: The GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920, FTO intron; rs2834826, RUNX1 intergenic). High-throughput targeted sequencing indicated that an FTO coding variant (rs79206939, p.A134T) linked to rs16957920 is associated with thiopurine-induced leukopenia. This result was further validated in two replication cohorts (combined p=1.3×10-8, OR=4.3). The frequency of FTOp.A134T is 5.1% in Koreans but less than 0.1% in Western populations. The p.A134T variation reduced FTO activity by 65% in the nucleotide demethylase assay. In vivo experiments revealed that Fto-/- and Fto+/- mice were more susceptible to thiopurine-induced myelosuppression than wild-type mice. CONCLUSIONS: The results suggest that the hypomorphic FTOp.A134T variant is associated with thiopurine-induced leukopenia. These results shed light on the novel physiological role of FTO and provide a potential pharmacogenetic biomarker for thiopurine therapy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Entities:
Keywords:
AZATHIOPRINE; DRUG TOXICITY; GENETICS; INFLAMMATORY BOWEL DISEASE