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

Han Sang Kim, Jae Hee Cheon, Eun Suk Jung, Joonhee Park, Sowon Aum, Soo Jung Park, Sungho Eun, Jinu Lee, Ulrich Rüther, Giles S.H. Yeo, Marcella Ma, Kyong Soo Park, Takeo Naito, Yoichi Kakuta, Ji Hyun Lee, Won Ho Kim, Min Goo Lee

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13 Citations (Scopus)

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 â '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 â '/â ' and Fto +/â ' 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.

Original languageEnglish
Pages (from-to)1926-1935
Number of pages10
JournalGut
Volume66
Issue number11
DOIs
Publication statusPublished - 2017 Nov 1

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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    Kim, H. S., Cheon, J. H., Jung, E. S., Park, J., Aum, S., Park, S. J., Eun, S., Lee, J., Rüther, U., Yeo, G. S. H., Ma, M., Park, K. S., Naito, T., Kakuta, Y., Lee, J. H., Kim, W. H., & Lee, M. G. (2017). A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD. Gut, 66(11), 1926-1935. https://doi.org/10.1136/gutjnl-2016-311921