Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression

Zuzana Zelinkova; Luc J J Derijks; Pieter C F Stokkers; Esther W M Vogels; Antoine H C van Kampen; Wouter L Curvers; Danny Cohn; Sander J H van Deventer; Daniël W Hommes

doi:10.1016/j.cgh.2005.10.019

Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression

Zuzana Zelinkova
, Luc J J Derijks
, Pieter C F Stokkers
, Esther W M Vogels
, Antoine H C van Kampen
, Wouter L Curvers
, Danny Cohn
, Sander J H van Deventer
, Daniël W Hommes

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND & AIMS: The use of azathioprine (AZA) in inflammatory bowel disease (IBD) patients is limited by toxicity, which occurs in up to 20% of treated patients. Mutations in the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genes have been associated with the occurrence of AZA-related toxicity. The aim of our study was to determine the relative contribution of ITPA and TPMT mutations to the development of toxicity induced by AZA treatment in IBD patients.

METHODS: ITPA(94C>A, IVS2+21A>C) and TPMT (238G>C, 460G>A, and 719A>G) genotypes were assessed in 262 IBD patients (159 females, 103 males; 67 patients with ulcerative colitis, 195 patients with Crohn's disease) treated with AZA and were correlated with the development of leukopenia and hepatotoxicity.

RESULTS: Leukopenia (leukocyte count, <3.0 x 10(9)/L) was observed in 4.6% of treated patients. The frequencies of mutant ITPA 94C>A and TPMT alleles were significantly higher in the leukopenic population compared with patients without leukopenia (16.7% and 5.4%, respectively, for ITPA 94C>A, and 20.8% and 4%, respectively, for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A odds ratio, 3.504; 95% confidence interval, 1.119-10.971 (P = .046); TPMT odds ratio, 6.316; 95% confidence interval, 2.141-18.634 (P = .004). Neither TPMT nor ITPA genotype predicted hepatotoxicity.

CONCLUSIONS: ITPA 94C>A and TPMT polymorphisms are associated with AZA-related leukopenia in IBD patients.

Original language	English
Pages (from-to)	44-9
Number of pages	6
Journal	Clinical gastroenterology and hepatology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1016/j.cgh.2005.10.019
Publication status	Published - Jan 2006
Externally published	Yes

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Azathioprine/adverse effects
Chemical and Drug Induced Liver Injury/etiology
Cross-Sectional Studies
Female
Genotype
Humans
Immunosuppressive Agents/adverse effects
Inflammatory Bowel Diseases/drug therapy
Leukopenia/chemically induced
Male
Methyltransferases/genetics
Middle Aged
Mutation
Polymorphism, Genetic
Pyrophosphatases/genetics
Retrospective Studies
Inosine Triphosphatase

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10.1016/j.cgh.2005.10.019

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Zelinkova, Z., Derijks, L. J. J., Stokkers, P. C. F., Vogels, E. W. M., van Kampen, A. H. C., Curvers, W. L., Cohn, D., van Deventer, S. J. H., & Hommes, D. W. (2006). Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clinical gastroenterology and hepatology, 4(1), 44-9. https://doi.org/10.1016/j.cgh.2005.10.019

@article{fe95574d3e0742a2855e5c6393327136,

title = "Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression",

abstract = "BACKGROUND \& AIMS: The use of azathioprine (AZA) in inflammatory bowel disease (IBD) patients is limited by toxicity, which occurs in up to 20\% of treated patients. Mutations in the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genes have been associated with the occurrence of AZA-related toxicity. The aim of our study was to determine the relative contribution of ITPA and TPMT mutations to the development of toxicity induced by AZA treatment in IBD patients.METHODS: ITPA(94C>A, IVS2+21A>C) and TPMT (238G>C, 460G>A, and 719A>G) genotypes were assessed in 262 IBD patients (159 females, 103 males; 67 patients with ulcerative colitis, 195 patients with Crohn's disease) treated with AZA and were correlated with the development of leukopenia and hepatotoxicity.RESULTS: Leukopenia (leukocyte count, <3.0 x 10(9)/L) was observed in 4.6\% of treated patients. The frequencies of mutant ITPA 94C>A and TPMT alleles were significantly higher in the leukopenic population compared with patients without leukopenia (16.7\% and 5.4\%, respectively, for ITPA 94C>A, and 20.8\% and 4\%, respectively, for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A odds ratio, 3.504; 95\% confidence interval, 1.119-10.971 (P = .046); TPMT odds ratio, 6.316; 95\% confidence interval, 2.141-18.634 (P = .004). Neither TPMT nor ITPA genotype predicted hepatotoxicity.CONCLUSIONS: ITPA 94C>A and TPMT polymorphisms are associated with AZA-related leukopenia in IBD patients.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Azathioprine/adverse effects, Chemical and Drug Induced Liver Injury/etiology, Cross-Sectional Studies, Female, Genotype, Humans, Immunosuppressive Agents/adverse effects, Inflammatory Bowel Diseases/drug therapy, Leukopenia/chemically induced, Male, Methyltransferases/genetics, Middle Aged, Mutation, Polymorphism, Genetic, Pyrophosphatases/genetics, Retrospective Studies, Inosine Triphosphatase",

author = "Zuzana Zelinkova and Derijks, \{Luc J J\} and Stokkers, \{Pieter C F\} and Vogels, \{Esther W M\} and \{van Kampen\}, \{Antoine H C\} and Curvers, \{Wouter L\} and Danny Cohn and \{van Deventer\}, \{Sander J H\} and Hommes, \{Dani{\"e}l W\}",

year = "2006",

month = jan,

doi = "10.1016/j.cgh.2005.10.019",

language = "English",

volume = "4",

pages = "44--9",

journal = "Clinical gastroenterology and hepatology",

issn = "1542-3565",

publisher = "W.B. Saunders",

number = "1",

}

Zelinkova, Z, Derijks, LJJ, Stokkers, PCF, Vogels, EWM, van Kampen, AHC, Curvers, WL, Cohn, D, van Deventer, SJH & Hommes, DW 2006, 'Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression', Clinical gastroenterology and hepatology, vol. 4, no. 1, pp. 44-9. https://doi.org/10.1016/j.cgh.2005.10.019

TY - JOUR

T1 - Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression

AU - Zelinkova, Zuzana

AU - Derijks, Luc J J

AU - Stokkers, Pieter C F

AU - Vogels, Esther W M

AU - van Kampen, Antoine H C

AU - Curvers, Wouter L

AU - Cohn, Danny

AU - van Deventer, Sander J H

AU - Hommes, Daniël W

PY - 2006/1

Y1 - 2006/1

N2 - BACKGROUND & AIMS: The use of azathioprine (AZA) in inflammatory bowel disease (IBD) patients is limited by toxicity, which occurs in up to 20% of treated patients. Mutations in the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genes have been associated with the occurrence of AZA-related toxicity. The aim of our study was to determine the relative contribution of ITPA and TPMT mutations to the development of toxicity induced by AZA treatment in IBD patients.METHODS: ITPA(94C>A, IVS2+21A>C) and TPMT (238G>C, 460G>A, and 719A>G) genotypes were assessed in 262 IBD patients (159 females, 103 males; 67 patients with ulcerative colitis, 195 patients with Crohn's disease) treated with AZA and were correlated with the development of leukopenia and hepatotoxicity.RESULTS: Leukopenia (leukocyte count, <3.0 x 10(9)/L) was observed in 4.6% of treated patients. The frequencies of mutant ITPA 94C>A and TPMT alleles were significantly higher in the leukopenic population compared with patients without leukopenia (16.7% and 5.4%, respectively, for ITPA 94C>A, and 20.8% and 4%, respectively, for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A odds ratio, 3.504; 95% confidence interval, 1.119-10.971 (P = .046); TPMT odds ratio, 6.316; 95% confidence interval, 2.141-18.634 (P = .004). Neither TPMT nor ITPA genotype predicted hepatotoxicity.CONCLUSIONS: ITPA 94C>A and TPMT polymorphisms are associated with AZA-related leukopenia in IBD patients.

AB - BACKGROUND & AIMS: The use of azathioprine (AZA) in inflammatory bowel disease (IBD) patients is limited by toxicity, which occurs in up to 20% of treated patients. Mutations in the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) genes have been associated with the occurrence of AZA-related toxicity. The aim of our study was to determine the relative contribution of ITPA and TPMT mutations to the development of toxicity induced by AZA treatment in IBD patients.METHODS: ITPA(94C>A, IVS2+21A>C) and TPMT (238G>C, 460G>A, and 719A>G) genotypes were assessed in 262 IBD patients (159 females, 103 males; 67 patients with ulcerative colitis, 195 patients with Crohn's disease) treated with AZA and were correlated with the development of leukopenia and hepatotoxicity.RESULTS: Leukopenia (leukocyte count, <3.0 x 10(9)/L) was observed in 4.6% of treated patients. The frequencies of mutant ITPA 94C>A and TPMT alleles were significantly higher in the leukopenic population compared with patients without leukopenia (16.7% and 5.4%, respectively, for ITPA 94C>A, and 20.8% and 4%, respectively, for TPMT). Moreover, the ITPA 94C>A and TPMT mutations predicted leukopenia: ITPA 94C>A odds ratio, 3.504; 95% confidence interval, 1.119-10.971 (P = .046); TPMT odds ratio, 6.316; 95% confidence interval, 2.141-18.634 (P = .004). Neither TPMT nor ITPA genotype predicted hepatotoxicity.CONCLUSIONS: ITPA 94C>A and TPMT polymorphisms are associated with AZA-related leukopenia in IBD patients.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Azathioprine/adverse effects

KW - Chemical and Drug Induced Liver Injury/etiology

KW - Cross-Sectional Studies

KW - Female

KW - Genotype

KW - Humans

KW - Immunosuppressive Agents/adverse effects

KW - Inflammatory Bowel Diseases/drug therapy

KW - Leukopenia/chemically induced

KW - Male

KW - Methyltransferases/genetics

KW - Middle Aged

KW - Mutation

KW - Polymorphism, Genetic

KW - Pyrophosphatases/genetics

KW - Retrospective Studies

KW - Inosine Triphosphatase

U2 - 10.1016/j.cgh.2005.10.019

DO - 10.1016/j.cgh.2005.10.019

M3 - Article

C2 - 16431304

SN - 1542-3565

VL - 4

SP - 44

EP - 49

JO - Clinical gastroenterology and hepatology

JF - Clinical gastroenterology and hepatology

IS - 1

ER -

Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression

Abstract

Keywords

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