A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia

作者：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 Inchul; McGovern Dermot P B; Liu Jianjun; Song Kyuyoung^*

来源：Nature Genetics, 2014, 46(9): 1017-+.

DOI：10.1038/ng.3060

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%26apos;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-combined = 4.88 x 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 x 10(-4)). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.

• 出版日期2014-9