NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.
NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.
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DOI：
10.1007/s00535-018-1486-7
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发表时间：
2018-09
影响因子：
6.3
通讯作者：
MENDEL study group
中科院分区：
文献类型：
--
作者：
Kakuta Y;Kawai Y;Okamoto D;Takagawa T;Ikeya K;Sakuraba H;Nishida A;Nakagawa S;Miura M;Toyonaga T;Onodera K;Shinozaki M;Ishiguro Y;Mizuno S;Takahara M;Yanai S;Hokari R;Nakagawa T;Araki H;Motoya S;Naito T;Moroi R;Shiga H;Endo K;Kobayashi T;Naganuma M;Hiraoka S;Matsumoto T;Nakamura S;Nakase H;Hisamatsu T;Sasaki M;Hanai H;Andoh A;Nagasaki M;Kinouchi Y;Shimosegawa T;Masamune A;Suzuki Y;MENDEL study group
尽管NUDT 15变异体显示与亚洲人中硫嘌呤诱导的不良事件（AE）显著相关，但仍不清楚NUDT 15的哪些变异体或是否应测试其他遗传变异体以预测AE。为了阐明临床上使用的最佳药物遗传学测试，我们进行了NUDT 15变体和单倍型与AE的关联研究、全基因组关联研究（GWAS）以发现其他变体，并进行了ROC分析以选择预测严重AE的模型。总体而言，2630例炎症性肠病（IBD）患者入组并对NUDT 15密码子139进行基因分型; 1291例患者接受硫嘌呤治疗。在970名患者中分析了双倍型，并使用群体优化的基因分型阵列和插补对1221名患者进行了AE的GWAS。我们证实了NUDT 15 p.Arg139Cys与白细胞减少症和脱发的相关性（p = 2.20E−63，1.32E−69，OR = 6.59，12.1，分别），并发现了与消化道症状的新关联（p = 6.39E−04，OR = 1.89）。至白细胞减少症的时间显著缩短，并且当诊断出白细胞减少症时，Arg/Cys和Cys/Cys组的巯嘌呤剂量显著低于Arg/Arg组。在GWAS中，未发现与硫嘌呤诱导的AE相关的其他变体。尽管白细胞减少症频率与基于双体型的估计酶活性具有强相关性，（r2 = 0.926，p = 0.0087），双倍型与密码子139的AUC在预测重度AE方面没有显著差异（急性重度白细胞减少症的AUC分别为0.916、0.921，重度脱发的AUC分别为0.990、0.991）。NUDT 15密码子139的基因分型足以预测日本IBD患者的急性重度白细胞减少症和脱发。本文的在线版本（10.1007/s 00535 -018-1486-7）包含补充材料，可供授权用户使用。
Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E−63, 1.32E−69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E−04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD. The online version of this article (10.1007/s00535-018-1486-7) contains supplementary material, which is available to authorized users.
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影响因子：
6.3
作者：
Matsuoka K;Kobayashi T;Ueno F;Matsui T;Hirai F;Inoue N;Kato J;Kobayashi K;Kobayashi K;Koganei K;Kunisaki R;Motoya S;Nagahori M;Nakase H;Omata F;Saruta M;Watanabe T;Tanaka T;Kanai T;Noguchi Y;Takahashi KI;Watanabe K;Hibi T;Suzuki Y;Watanabe M;Sugano K;Shimosegawa T
通讯作者：
Shimosegawa T
影响因子：
30.8
作者：
Loh, Po-Ru;Danecek, Petr;Palamara, Pier Francesco;Fuchsberger, Christian;Reshef, Yakir A.;Finucane, Hilary K.;Schoenherr, Sebastian;Forer, Lukas;McCarthy, Shane;Abecasis, Goncalo R.;Durbin, Richard;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
3.6
作者：
Diergaarde, Brenda;Brand, Randall;Whitcomb, David C.
通讯作者：
Whitcomb, David C.
DOI：
10.1111/j.1440-1746.2009.05917.x
发表时间：
2009-07-01
影响因子：
4.1
作者：
Takatsu, Noritaka;Matsui, Toshiyuki;Yao, Kenshi
通讯作者：
Yao, Kenshi