Pharmacogeomic implications of population diversity in Latin America: TPMT and NUDT15 polymorphisms and thiopurine dosing.

TPMT and NUDT15 polymorphisms are major determinants of tolerance to thiopurine drugs used in leukemias and nonmalignant immunologic disorders. We adopted an extreme discordant phenotype approach to explore the impact of Native American versus European ancestry on the distribution of TPMT and NUDT15 polymorphisms, and inferred metabolic phenotypes in the 1000 Genomes Ad Mixed American superpopulation. Significant differences were observed in the distribution of TPMT and NUDT15 haplotypes (star alleles) between individuals with predominant (>70%) European versus Native ancestry. The largest difference is related to NUDT15 rs116855232. Based on the combined TPMT/NUDT15 metabolic phenotypes, the Clinical Pharmacogenetics Implementation Consortium recommendations for thiopurine dose adjustment applies to 40.1% of individuals with major Native American ancestry, compared to 12.8% of individuals with predominantly European ancestry. These findings may be relevant to the adoption and interpretation of pharmacogenetic tests for thiopurine drugs across Latin America peoples with different European and Native-American ancestries.