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Thiopurine S-methyltransferase ( TPMT) polymorphisms affect the enzyme's activity and are predictive for the efficacy and toxicity of thiopurine treatment of acute lymphoblastic leukemia (ALL), autoimmune diseases and organ transplants. Because inter-ethnic differences in the distribution of these polymorphisms have been documented, we sequenced the TMPT gene in 95 Guatemalans, yet identified no new alleles. We also determined the frequency of the TPMT*2 , *3A , *3B and *3C alleles in 270 admixed and 177 indigenous pediatric patients with ALL and healthy subjects from Guatemala using TaqMan assays and DNA sequencing. Among the 447 subjects genotyped, 10.0 % of the ALL cases and 13.6 % of the healthy controls were heterozygous for one of the four TPMT variants screened. The genotype frequencies in ALL and control populations were 0.7 and 1.7 % for TPMT*1/*2, 7.4 and 10 % for TPMT*1/*3A, 0.3 and 0 % for TPMT*1/*B, and 1.5 and 1.1 % for TPMT*1/*C, respectively ( p = 0.30). No statistically significant differences between admixed and indigenous ALL ( p = 0.67) or controls ( p = 0.41) groups were detected; however, 17 % of the admixed healthy group bore one TPMT mutant allele, and they have one of the highest reported frequencies of TPMT mutant allele carriers. Because of the clinical implications of these variants for therapeutic response, TPMT allele testing should be considered in all Guatemalan patients to reduce adverse side-effects from thiopurine drug treatments. [ABSTRACT FROM AUTHOR]

Abstract  Polymorphisms at the thiopurine S-methyltransferase coding gene (TPMT) determine enzyme activity and consequently, the development of toxicity secondary to thiopurines. Methods A total of 108 DNA samples from volunteer donors and 39 from patients with acute lymphoblastic leukemia (ALL) were analyzed. Genomic DNA from peripheral blood leukocytes was isolated by standard methods. TPMT gene fragments were amplified by PCR for exons 5, 7, and 10. Thereafter, these were analyzed by DHPLC for the most frequent mutant TPMT alleles. Results No elution profiles on DHPLC analysis, different from those previously reported, were documented. Frequency of functional allele polymorphisms was 17.6%, being the most frequent *3A (n = 13; 4.4%), followed by *3B (n = 5; 1.7%), *3C (n = 5; 1.7%), and *2 (n = 3; 1.0%). From 39 ALL patients, 22 were treated with thiopurines, and five from 10 with a functional polymorphism developed hematological toxicity (4 mild, 1 severe in a patient referred to our Hospital after developing pancytopenia while on treatment with thiopurine). Conclusions This is the first analysis of the polymorphisms at this gene in Mexican population. Since a direct relation has been documented within functional polymorphisms and enzyme activity, and DHPLC is a highly sensitive, rapid and efficient method, feasible to realize in any phase during the treatment of ALL patients, the routine typing of TPMT polymorphisms in the patients with ALL has been set in our Institution. [ABSTRACT FROM AUTHOR]