RGD Reference Report - Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia. - Rat Genome Database

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Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia.

Authors: Zgheib, NK  Akra-Ismail, M  Aridi, C  Mahfouz, R  Abboud, MR  Solh, H  Muwakkit, SA 
Citation: Zgheib NK, etal., Pharmacogenet Genomics. 2014 Aug;24(8):387-96. doi: 10.1097/FPC.0000000000000069.
RGD ID: 11080979
Pubmed: PMID:25007187   (View Abstract at PubMed)
DOI: DOI:10.1097/FPC.0000000000000069   (Journal Full-text)

BACKGROUND: The aim of this study is to analyze polymorphisms in genes involved in 6-mercaptopurine detoxification (TPMT); methotrexate (MTX) metabolism including ABCB1 (or MDR1), ABCC2, SLC19A1 (or RFC1), and SLCO1B1; and the MTX effect mainly MTHFR and TYMS, and to assess whether these polymorphisms are predictors of treatment toxicity and/or MTX clearance. MATERIALS AND METHODS: This study included 127 Lebanese acute lymphoblastic leukemia patients, of whom 117 were treated following the St Jude's Children Research Hospital protocol. Genotyping was performed using real-time PCR or restriction fragment length polymorphism. MTX levels were measured using a polarization fluorescence assay from Roche. MTX clearance was estimated on the basis of all available MTX levels measured after high-dose MTX treatment during the consolidation phase. RESULTS: Five variants in four genes (MTHFR, ABCB1, ABCC2, and TYMS) were shown to be associated with toxicity, but neither was associated with MTX pharmacokinetic parameters. For instance, during the consolidation phase, a statistically significant association was found between MTHFR rs1801133 variant allele carriers and a decrease in hemoglobin levels [odds ratio (OR)=3.057; 95% confidence interval (CI): 1.217; 7.680]. In addition, a statistically significant association was found among neutropenia (absolute neutrophil count<500) and variant allele carriers of ABCB1 rs1045642 (OR=5.174; 95% CI: 1.674; 15.989) and ABCB1 rs1128503 (OR=3.364; 95% CI: 1.257; 9.004), respectively. ABCC2 rs717620 variant allele carriers needed significantly more time to reach a MTX level below 0.1 micromol/l (beta=5.122; 95% CI: 1.412; 8.831). During the continuation phase, a statistically significant association was found between ABCC2 rs717620 and TYMS 28-bp tandem repeats carriers with the need to decrease weekly MTX doses (beta=-4.905; 95% CI: -9; -0.809 and beta=-5.770; 95% CI: -10.138; -1.403), respectively. CONCLUSION: Genotyping for MTHFR, ABCB1, ABCC2, and TYMS polymorphisms may be useful in identifying patients at risk of increased MTX toxicity and the need for dose optimization before treatment initiation.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ABCC2Humanacute lymphoblastic leukemia treatmentIAGP DNA:SNPs: :rs717620(human)RGD 
Abcc2Ratacute lymphoblastic leukemia treatmentISOABCC2 (Homo sapiens)DNA:SNPs: :rs717620(human)RGD 
Abcc2Mouseacute lymphoblastic leukemia treatmentISOABCC2 (Homo sapiens)DNA:SNPs: :rs717620(human)RGD 
TYMSHumanacute lymphoblastic leukemia treatmentIAGP DNA:repeats: : rs347430033(human)RGD 
TymsRatacute lymphoblastic leukemia treatmentISOTYMS (Homo sapiens)DNA:repeats: : rs347430033(human)RGD 
TymsMouseacute lymphoblastic leukemia treatmentISOTYMS (Homo sapiens)DNA:repeats: : rs347430033(human)RGD 
MTHFRHumananemia susceptibilityIAGP associated with Precursor Cell Lymphoblastic Leukemia-Lymphoma and DNA:SNP:: rs1801133(human) RGD 
MthfrRatanemia susceptibilityISOMTHFR (Homo sapiens)associated with Precursor Cell Lymphoblastic Leukemia-Lymphoma and DNA:SNP:: rs1801133(human) RGD 
MthfrMouseanemia susceptibilityISOMTHFR (Homo sapiens)associated with Precursor Cell Lymphoblastic Leukemia-Lymphoma and DNA:SNP:: rs1801133(human) RGD 
ABCB1HumanDrug-induced Neutropenia susceptibilityIAGP associated with Precursor Cell Lymphoblastic Leukemia-Lymphoma more ...RGD 
Abcb1aRatDrug-induced Neutropenia susceptibilityISOABCB1 (Homo sapiens)associated with Precursor Cell Lymphoblastic Leukemia-Lymphoma more ...RGD 
Abcb1aMouseDrug-induced Neutropenia susceptibilityISOABCB1 (Homo sapiens)associated with Precursor Cell Lymphoblastic Leukemia-Lymphoma more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcb1a  (ATP binding cassette subfamily B member 1A)
Abcc2  (ATP binding cassette subfamily C member 2)
Mthfr  (methylenetetrahydrofolate reductase)
Tyms  (thymidylate synthetase)

Genes (Mus musculus)
Abcb1a  (ATP-binding cassette, sub-family B member 1A)
Abcc2  (ATP-binding cassette, sub-family member 2)
Mthfr  (methylenetetrahydrofolate reductase)
Tyms  (thymidylate synthase)

Genes (Homo sapiens)
ABCB1  (ATP binding cassette subfamily B member 1)
ABCC2  (ATP binding cassette subfamily C member 2)
MTHFR  (methylenetetrahydrofolate reductase)
TYMS  (thymidylate synthetase)


Additional Information