A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD
Authors
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
Adolescent ; Adult ; Aged ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Animals ; Azathioprine/adverse effects* ; Azathioprine/therapeutic use ; Case-Control Studies ; Cohort Studies ; Female ; Genetic Markers ; Genome-Wide Association Study ; High-Throughput Nucleotide Sequencing ; Humans ; Immunosuppressive Agents/adverse effects* ; Immunosuppressive Agents/therapeutic use ; Inflammatory Bowel Diseases/drug therapy* ; Inflammatory Bowel Diseases/genetics ; Leukopenia/chemically induced* ; Leukopenia/genetics ; Male ; Mercaptopurine/adverse effects* ; Mercaptopurine/therapeutic use ; Mice ; Mice, Knockout ; Middle Aged ; Polymorphism, Single Nucleotide* ; Republic of Korea ; Sequence Analysis, DNA ; Young Adult
Keywords
AZATHIOPRINE ; DRUG TOXICITY ; GENETICS ; INFLAMMATORY BOWEL DISEASE
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.