@article {Kim1926, author = {Han Sang Kim and Jae Hee Cheon and Eun Suk Jung and Joonhee Park and Sowon Aum and Soo Jung Park and Sungho Eun and Jinu Lee and Ulrich R{\"u}ther and Giles S H Yeo and Marcella Ma and Kyong Soo Park and Takeo Naito and Yoichi Kakuta and Ji Hyun Lee and Won Ho Kim and Min Goo Lee}, title = {A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD}, volume = {66}, number = {11}, pages = {1926--1935}, year = {2017}, doi = {10.1136/gutjnl-2016-311921}, publisher = {BMJ Publishing Group}, 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{\texttimes}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.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/66/11/1926}, eprint = {https://gut.bmj.com/content/66/11/1926.full.pdf}, journal = {Gut} }