Dataset Information

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.

ABSTRACT: BACKGROUND: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. METHODS: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. RESULTS: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). CONCLUSIONS:Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

SUBMITTER: Kakuta Y

PROVIDER: S-EPMC6132901 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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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.

Kakuta Yoichi Y Kawai Yosuke Y Okamoto Daisuke D Takagawa Tetsuya T Ikeya Kentaro K Sakuraba Hirotake H Nishida Atsushi A Nakagawa Shoko S Miura Miki M Toyonaga Takahiko T Onodera Kei K Shinozaki Masaru M Ishiguro Yoh Y Mizuno Shinta S Takahara Masahiro M Yanai Shunichi S Hokari Ryota R Nakagawa Tomoo T Araki Hiroshi H Motoya Satoshi S Naito Takeo T Moroi Rintaro R Shiga Hisashi H Endo Katsuya K Kobayashi Taku T Naganuma Makoto M Hiraoka Sakiko S Matsumoto Takayuki T Nakamura Shiro S Nakase Hiroshi H Hisamatsu Tadakazu T Sasaki Makoto M Hanai Hiroyuki H Andoh Akira A Nagasaki Masao M Kinouchi Yoshitaka Y Shimosegawa Tooru T Masamune Atsushi A Suzuki Yasuo Y

Journal of gastroenterology 20180619 9

<h4>Background</h4>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 pr ...[more]

PMID: 29923122

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Project description:ImportanceUse of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).ObjectiveTo identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, setting, and participantsCase-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.ExposuresGenetic variants associated with TIM.Main outcomes and measuresThiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.ResultsAmong 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.Conclusions and relevanceAmong patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Dataset Information

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.

Publications

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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