Genetic variants of thiopurine and folate metabolic pathways determine 6-MP-mediated hematological toxicity in childhood ALL. (July 2012)

• Record Type: Journal Article
• Authors: Dorababu, Patchva; Naushad, Shaik Mohammad; Linga, Vijay Gandhi; Gundeti, Sadashivudu; Nagesh, Narayana; Kutala, Vijay Kumar; Reddanna, Pallu; Digumarti, Raghunadharao
• Is Part Of: Pharmacogenomics. Volume 13:Number 9(2012)
• Page Start: 1001
• Page End: 1008
• Publication Date: 2012-07
• Subjects: 6-mercaptopurine -- childhood acute lymphoblastic leukemia -- folate metabolism -- haplotype -- pharmacogenetics -- S-adenosyl methionine -- thiopurine methyltransferase; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.12.70
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: The rationale of this study was to explore the contribution of genetic variants of the folate pathway to toxicity of 6-mercaptopurine (6-MP)-mediated hematological toxicity in children with acute lymphoblastic leukemia (ALL) and to explore the interaction of these variants with TPMT and ITPA haplotypes using multifactor dimensionality reduction analysis.Materials & methods: Children with ALL (n = 96) were screened for GCPII C1561T, RFC1 G80A, cSHMT C1420T, TYMS 5´-UTR 2R3R, TYMS 3´-UTR ins6/del6, MTHFR C677T, MTR A2756G polymorphisms using PCR-RFLP and PCR-amplified fragment length polymorphism techniques.Results: GCPII C1561T showed independent association with toxicity. The following synergetic interactions appeared to increase the toxicity of 6-mercaptopurine: TPMT*12 × RFC1 G80A; TPMT CTTAT haplotype × RFC1 G80A; TPMT CTTAT haplotype × RFC1 G80A × TYMS 2R3R. The genetic variants of thiopurine and folate pathway cumulatively appeared to increase the predictability of toxicity (r 2 = 0.41) in a multiple linear regression model. For the observed toxicity grades of 1, 2, 3 and 4, the respective predicted toxicity grades were 1.65 ± 0.29, 1.68 ± 0.24, 2.56 ± 0.58 and 2.99 ± 1.03, ptrend < 0.0001. Conclusion: Gene–gene interaction between thiopurine and folate pathways inflate the 6-MP-mediated toxicity in Indian children with ALL illustrating the importance of ethnicity in the toxicity of 6-MP. Original submitted 3 January 2012; Revision submitted 23 April 2012