A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.
A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia.
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DOI：
10.1038/ng.3060
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发表时间：
2014-09
期刊：
影响因子：
30.8
通讯作者：
Song K
中科院分区：
文献类型：
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作者：
Yang SK;Hong M;Baek J;Choi H;Zhao W;Jung Y;Haritunians T;Ye BD;Kim KJ;Park SH;Park SK;Yang DH;Dubinsky M;Lee I;McGovern DP;Liu J;Song K
巯基嘌呤治疗，通常用于自身免疫性疾病，可并发危及生命的白细胞减少症。这种白细胞减少症与TPMT（编码硫嘌呤S-甲基转移酶）的遗传变异有关。尽管亚洲人TPMT突变的频率较低，但亚洲人硫嘌呤诱导的白细胞减少症的发生率高于欧洲血统的个体。在这里，我们进行了免疫芯片为基础的2阶段的关联研究，在978名韩国受试者与克罗恩病治疗硫嘌呤。我们在NUDT 15（编码p.Arg139Cys）中发现了一个非同义SNP，该SNP与硫嘌呤诱导的早期白细胞减少症密切相关（比值比（OR）= 35.6; Pcombined = 4.88 × 10−94）。在韩国人中，该变异体对硫嘌呤诱导的早期白细胞减少症的敏感性和特异性分别为89.4%和93.2%（TPMT变异体为12.1%和97.6%）。虽然罕见，但该SNP也与欧洲血统炎症性肠病受试者中硫嘌呤诱导的白细胞减少症密切相关（OR = 9.50; P = 4.64 × 10−4）。因此，NUDT 15是不同人群中巯基嘌呤诱导的白细胞减少症的药物遗传学决定因素。
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; Pcombined = 4.88 × 10−94). 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 × 10−4). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.