Dataset Information

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

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.

SUBMITTER: Yang SK

PROVIDER: S-EPMC4999337 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Yang Suk-Kyun SK Hong Myunghee M Baek Jiwon J Choi Hyunchul H Zhao Wanting W Jung Yusun Y Haritunians Talin T Ye Byong Duk BD Kim Kyung-Jo KJ Park Sang Hyoung SH Park Soo-Kyung SK Yang Dong-Hoon DH Dubinsky Marla M Lee Inchul I McGovern Dermot P B DP Liu Jianjun J Song Kyuyoung K

Nature genetics 20140810 9

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 t ...[more]

PMID: 25108385

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Project description:Background and aim:Despite several studies being conducted to examine the associations between the NUDT15 R139C polymorphism and thiopurine-induced leukopenia in the Asian population, the results remain inconsistent. This meta-analysis determined the risk of thiopurine-induced leukopenia conferred by the NUDT15 R139C polymorphism. Materials and methods:All eligible studies published in English up to May 2018 were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library. Pooled OR and 95% CI were calculated using fixed- or random-effect model. Results:In all, total of 14 studies containing 918 patients and 2,341 controls were included; of these, 8 studies concerned inflammatory bowel disease (IBD) and 4 concerned acute lymphoblastic leukemia (ALL). Overall, the results indicated that the NUDT15 R139C polymorphism was associated with leukopenia induced by thiopurines (OR =9.04, 95% CI 6.05-13.50, P<0.001 for the dominant model; OR =24.26, 95% CI 11.38-51.71, P<0.001 for the recessive model; OR =7.60, 95% CI 4.97-11.61, P<0.001 for the CT vs TT model; OR =38.47, 95% CI 17.78-83.24, P<0.001 for the CC vs TT model). In subgroup analyses, significant associations were found among patients with IBD (OR =7.57, 95% CI 5.16-11.12, P<0.001 for the dominant model), ALL (OR =13.13, 95% CI 3.43-50.23 P<0.001 for the dominant model), and other diseases (OR =31.22, 95% CI 1.20-814.07, P=0.04 for the dominant model). In addition, the R139C variant was strongly associated with early (<8 weeks) (OR =15.53, 95% CI 7.91-30.50, P<0.001 for the dominant model) and late leukopenia (?8 weeks) (OR =2.92, 95% CI 2.01-4.24, P<0.001 for the dominant model). Moreover, these findings were sufficiently robust when studies without Hardy-Weinberg equilibrium test were excluded. Conclusion:This meta-analysis verified the strong association between the NUDT15 R139C polymorphism and thiopurine-induced leukopenia (both early and late leukopenia) in an Asian population with IBD, ALL, and other diseases. NUDT15 R139C genotyping should be prioritized to predict leukopenia among Asians.

Project description:BackgroundNUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure.MethodsWhole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age- and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p < 0.01, N = 188 for discovery) and validate (p < 0.05, N = 52 for replication) candidate variants for the tolerated last-cycle 6-mercaptopurine (6-MP) dose intensity percentage (DIP). Both independent and additive effects of the candidate variants on well-known NUDT15 and TPMT were evaluated by multigene prediction models.ResultsAmong the 12 candidate variants from the discovery phase, the rs3821169 variant of the gene encoding Cysteine-Rich Transmembrane BMP Regulator 1 (CRIM1) was successfully replicated (p < 0.05). It showed high interethnic variability with an impressively high allele frequency in East Asians (T = 0.255) compared to Africans (0.001), Americans (0.02), Europeans (0.009), and South Asians (0.05). Homozygote carriers of the CRIM1 rs3821169 variant (N = 12, 5%) showed significantly lower last-cycle 6-MP DIPs in the discovery, replication, and combined cohorts (p = 0.025, 0.013, and 0.001, respectively). The traditional two-gene model (NUDT15 and TPMT) for predicting 6-MP DIP < 25% was outperformed by the three-gene model that included CRIM1, in terms of the area under the receiver operating characteristic curve (0.734 vs. 0.665), prediction accuracy (0.759 vs. 0.756), sensitivity (0.636 vs. 0.523), positive predictive value (0.315 vs. 0.288), and negative predictive value (0.931 vs. 0.913).ConclusionsThe CRIM1 rs3821169 variant is suggested to be an independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

Dataset Information

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

Publications

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

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