Genetic variants of thiopurine and folate metabolic pathways determine 6-MP-mediated hematological toxicity in childhood ALL

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 x RFC1 G80A; TPMT CTTAT haplotype x RFC1 G80A; TPMT CTTAT haplotype x RFC1 G80A x 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, p(trend) < 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.