Pharmacogenomics research and clinical implementation in Brazil

Abstract

We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV-positive carriers of UGT1A1*28 to severe atazanavir-induced hyperbilirubinaemia, intolerance to 5-fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV-infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG-IFN-α, and hypersensitivity reactions to abacavir in HIV-positive carriers of HLA-B*57:01. No prospective analyses of drug therapy outcomes or cost-effectiveness assessments of PGx-guided therapy were found. In conclusion, the limited adoption of PGx-informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA-B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), "race" or ethnicity.