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A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia
Yang, Suk-Kyun,Hong, Myunghee,Baek, Jiwon,Choi, Hyunchul,Zhao, Wanting,Jung, Yusun,Haritunians, Talin,Ye, Byong Duk,Kim, Kyung-Jo,Park, Sang Hyoung,Park, Soo-Kyung,Yang, Dong-Hoon,Dubinsky, Marla,Lee, Nature Pub. Co 2014 Nature genetics Vol.46 No.9
Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; P<SUB>combined</SUB> = 4.88 × 10<SUP>−94</SUP>). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10<SUP>−4</SUP>). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.
Hong, Myunghee,Ye, Byong Duk,Yang, Suk-Kyun,Jung, Seulgi,Lee, Ho-Su,Kim, Byoung Mok,Lee, Soo Bin,Hong, Jeonghoon,Baek, Jiwon,Park, Sang Hyoung,Han, Buhm,Li, Yi,Liu, Wenting,Haritunians, Talin,Taylor, Oxford University Press 2018 JOURNAL OF CROHNS AND COLITIS Vol.12 No.6
<P>Conclusions: Our findings of new loci not previously associated with IBD support the importance of studying inflammatory bowel disease genetics in diverse populations.</P>