RT Journal Article
SR Electronic
T1 A coding variant in <em>FTO</em> confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1926
OP 1935
DO 10.1136/gutjnl-2016-311921
VO 66
IS 11
A1 Han Sang Kim
A1 Jae Hee Cheon
A1 Eun Suk Jung
A1 Joonhee Park
A1 Sowon Aum
A1 Soo Jung Park
A1 Sungho Eun
A1 Jinu Lee
A1 Ulrich Rüther
A1 Giles S H Yeo
A1 Marcella Ma
A1 Kyong Soo Park
A1 Takeo Naito
A1 Yoichi Kakuta
A1 Ji Hyun Lee
A1 Won Ho Kim
A1 Min Goo Lee
YR 2017
UL http://gut.bmj.com/content/66/11/1926.abstract
AB 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.