A coding variant in <i>FTO</i> confers 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 of <i>FTO</i> (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, <i>FTO</i> intron; rs2834826, <i>RUNX1</i> intergenic). High-throughput targeted sequencing indicated that an <i>FTO</i> 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 <i>FTO</i> 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 <i>Fto^-/-</i> and <i>Fto^+/-</i> mice were more susceptible to thiopurine-induced myelosuppression than wild-type mice. The results suggest that the hypomorphic <i>FTO</i> 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.