A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Yang, S., Hong, M., Baek, J., Choi, H., Zhao, W., Jung, Y., Haritunians, T., Ye, B. D., Kim, K., Park, S. H., Park, S., Dubinsky, M., Yang, D., Lee, I., McGovern, D. P. B., Liu, J., & Song, K. Nature Genetics, 46(9):1017–1020, September, 2014.
doi  abstract   bibtex   
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(combined) = 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.
@article{yang_common_2014,
	title = {A common missense variant in {NUDT15} confers susceptibility to thiopurine-induced leukopenia},
	volume = {46},
	issn = {1546-1718},
	doi = {10.1038/ng.3060},
	abstract = {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(combined) = 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.},
	language = {eng},
	number = {9},
	journal = {Nature Genetics},
	author = {Yang, Suk-Kyun and Hong, Myunghee and Baek, Jiwon and Choi, Hyunchul and Zhao, Wanting and Jung, Yusun and Haritunians, Talin and Ye, Byong Duk and Kim, Kyung-Jo and Park, Sang Hyoung and Park, Soo-Kyung and Dubinsky, Marla and Yang, Dong-Hoon and Lee, Inchul and McGovern, Dermot P. B. and Liu, Jianjun and Song, Kyuyoung},
	month = sep,
	year = {2014},
	pmid = {25108385},
	pmcid = {PMC4999337},
	keywords = {Adolescent, Adult, Aged, Asian Continental Ancestry Group, Case-Control Studies, Child, Crohn Disease, Female, Genetic Predisposition to Disease, Humans, Leukopenia, Male, Methyltransferases, Middle Aged, Mutation, Missense, Polymorphism, Single Nucleotide},
	pages = {1017--1020},
}
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