| Autor: |
Kim, Han Sang, Cheon, Jae Hee, Jung, Eun Suk, Park, Joonhee, Aum, Sowon, Park, Soo Jung, Eun, Sungho, Lee, Jinu, Ruther, Ulrich, Yeo, Giles S H, Ma, Marcella, Park, Kyong Soo, Naito, Takeo, Kakuta, Yoichi, Lee, Ji Hyun, Kim, Won Ho, Lee, Min Goo |
| Zdroj: |
Gut; 2017, Vol. 66 Issue: 11 p1926-1935, 10p |
| Abstrakt: |
ObjectiveMyelosuppression 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.DesignA 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.ResultsThe GWAS identified two loci associated with thiopurine-induced leukopenia (rs16957920, FTOintron; rs2834826, RUNX1intergenic). High-throughput targeted sequencing indicated that an FTOcoding 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 FTOp.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.ConclusionsThe results suggest that the hypomorphic FTOp.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. |
| Databáze: |
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