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Gut. 2017 Nov;66(11):1926-1935. doi: 10.1136/gutjnl-2016-311921. Epub 2016 Aug 24.

A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD.

Author information

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.

KEYWORDS:

AZATHIOPRINE; DRUG TOXICITY; GENETICS; INFLAMMATORY BOWEL DISEASE

PMID:
27558924
DOI:
10.1136/gutjnl-2016-311921
[Indexed for MEDLINE]

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