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

作者：Kim Han Sang; Cheon Jae Hee; Jung Eun Suk; Park Joonhee; Aum Sowon; Park Soo Jung; Eun Sungho; Lee Jinu; Ruether Ulrich; Yeo Giles S H; Ma Marcella; Park Kyong Soo; Naito Takeo; Kakuta Yoichi; Lee Ji Hyun; Kim Won Ho^*; Lee Min Goo^*

来源：Gut, 2017, 66(11): 1926-1935.

DOI：10.1136/gutjnl-2016-311921

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 x 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.

• 出版日期2017-11