Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy

Colombel, Jean–Frédéric; Ferrari, Nicolas; H, Debuysère; Marteau, Philippe; Gendre, Jean–Pierre; Bonaz, Bruno; Soulé, Jean–Claude; Modigliani, R; Touze, Y; Catala, Pascale; Libersa, Christian; Broly, Franck

doi:10.1016/s0016-5085(00)70354-4

Cited by 570 publications

(414 citation statements)

References 28 publications

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“…On the other hand, we observed myelosuppression in 7 IBD patients with a wild TPMT genotype. This is supported by previous reports demonstrating that in IBD patients, bone-marrow suppression is not solely dependent on TPMT activity, but is also associated with other factors (15,16 …”

Section: Discussionsupporting

confidence: 89%

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

et al. 2008

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Section: Discussionsupporting

confidence: 89%

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

et al. 2008

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“…In a study with 41 leukopenic patients with CD treated with AZA, only 27% of the patients had one or two mutant TPMT alleles [128]. Myelosuppression was more often caused by other factors, such as viral infections, drugs interfering with AZA metabolism (allopurinol and 5-aminosalicylates) or causing bone marrow suppression by their own (trimethoprim-sulfamethoxazole, captopril and metronidazole).…”

Section: Geno-and Phenotypingmentioning

confidence: 99%

“…In IBD patients treated with thiopurines, up to 20% has to discontinue drug therapy due to the occurrence of adverse events [33][34][35]. The adverse events of thiopurines can be divided into dose-dependent, pharmacologically explainable events (type A) on one hand and dose-independent, hypersensitivity reactions (type B) on the other.…”

Section: Toxicitymentioning

confidence: 99%

“…However, the use of determining TPMT status, the exact moment when to perform genotyping and the clinical implications remain subject to discussion. Although TPMT genotyping seems to play a role in the prediction of early drug toxicity in patients who have not been previously exposed to AZA or 6-MP, the predictive value for myelotoxicity in patients established on thiopurines may in fact be limited [31][32][33]. Recently, also inosine triphosphate pyrophosphatase (ITPase) deficiency has been associated with thiopurine related toxicity.…”

Section: Genotypingmentioning

confidence: 99%

“…Also, no significant differences in ITPA and TPMT alleles could be observed between groups with and without hepatotoxicity. It has been demonstrated indisputably that homozygous TPMT mutants, like the one patient in our cohort, will experience early and severe myelosuppression due to extremely high 6-TGN levels when treated with standard AZA dosages and TPMT genoor phenotyping prior to initiation is the only way of identifying those at risk [22,31,33]. For heterozygous TPMT mutants however, an increased risk of developing bone marrow suppression mainly in a subsequent stage exists, but the correlation with TPMT geno-or phenotype is less pronounced [29,33].…”

Section: Genotypingmentioning

confidence: 99%

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Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

Derijks

Hommes²

2006

Curr Gastroenterol Rep

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Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Walker¹,

Harrison²,

Heap³

et al. 2019

JAMA

138

129

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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).OBJECTIVE To 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. EXPOSURES Genetic variants associated with TIM.MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 10 9 /L or less or a decline in absolute neutrophil cell count to 1.0 × 10 9 /L or less leading to a dose reduction or drug withdrawal. RESULTS Among 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 RELEVANCE Among 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.

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Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy

Cited by 570 publications

References 28 publications

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

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