title: A coding variant inFTOconfers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD.
abstract: 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.
  
  
  
  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 ofFTO(fat mass and obesity-associated) variant were examined both in vitro and in vivo.
  
  
  
  The GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920,FTOintron; rs2834826,RUNX1intergenic). High-throughput targeted sequencing indicated that anFTOcoding 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 ofFTOp.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 thatFto-/-andFto+/-mice were more susceptible to thiopurine-induced myelosuppression than wild-type mice.
  
  
  
  The results suggest that the hypomorphicFTOp.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.
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Han Sang
authors: HS
authors: Kim
authors: Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.|Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: Jae Hee
authors: JH
authors: Cheon
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: Eun Suk
authors: ES
authors: Jung
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors: Joonhee
authors: J
authors: Park
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors: Sowon
authors: S
authors: Aum
authors: Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: Soo Jung
authors: SJ
authors: Park
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors: Sungho
authors: S
authors: Eun
authors: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Inchon, Korea.
authors: Jinu
authors: J
authors: Lee
authors: Institute for Animal Developmental and Molecular Biology, Heinrich Heine University, Universitätsstr. 1, Düsseldorf, Germany.
authors: Ulrich
authors: U
authors: Rüther
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Giles S H
authors: GSH
authors: Yeo
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Marcella
authors: M
authors: Ma
authors: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors: Kyong Soo
authors: KS
authors: Park
authors: Division of Gastroenterology, Tohoku University Hospital, Miyagi, Japan.
authors: Takeo
authors: T
authors: Naito
authors: Division of Gastroenterology, Tohoku University Hospital, Miyagi, Japan.
authors: Yoichi
authors: 0000-0002-7042-009X
authors: Y
authors: Kakuta
authors: Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Korea.
authors: Ji Hyun
authors: JH
authors: Lee
authors: Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
authors: Won Ho
authors: WH
authors: Kim
authors: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Min Goo
authors: MG
authors: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics*; D000818:Animals; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D001379:Azathioprine
keywords: AZATHIOPRINE; DRUG TOXICITY; GENETICS; INFLAMMATORY BOWEL DISEASE