DPYD polymorphisms in Native populations from the Brazilian Amazon: the absence of the variants in currently recommended clinical genotyping panels.

Abstract

Objectives: We examined the distribution of clinically-relevant DPYD polymorphisms in Yanomami and Munduruku individuals, from Indigenous reservation areas in the Brazilian Amazon. The estimated proportion of Native ancestry exceeded 90% in all participants.

Methods: Eight DPYD single nucleotide variants (SNVs), including rs3918290, rs55886062, rs67376798, and rs75017182, widely recognized for their established associations with fluoropyrimidine-induced toxicity, plus rs115232898, rs2297595, rs1801265, and rs4294451 were genotyped, using Taqman probes. The distribution of haplotypes comprising rs1801265, rs2297595, and rs75017182 was assessed.

Results: Six variants, namely rs3918290, rs55886062, rs67376798, rs75017182, rs115232898, and rs2297595, were absent in the Yanomami and Munduruku cohorts. In striking contrast, rs1801265 and rs4294451 were common, with minor allele frequency (MAF) ranging between 0.41 (Yanomami) and 0.47 (Munduruku); these SNVs were in perfect (Yanomami) or strong (Munduruku) linkage disequilibrium. Regarding haplotypes comprising rs1801265, rs2297595, and rs75017182, only two were observed: one with the three reference alleles (T-A-C) and the other (C-A-C) with the variant rs1801265 C allele (frequency 41% in Yanomami and 47% in Munduruku).

Conclusion: The variants prioritized in the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, namely rs3918290, rs55886062, rs67376798, and rs75017182 were not detected in the Munduruku and Yanomami cohorts. Thus, pharmacogenetic screening of such variants would not provide reliable pharmacogenetic-guided recommendations for fluoropyrimidine dosing in the enrolled Native groups, and possibly other Amerindian ethnicities and admixed Latin American populations with major Native ancestry. DPYD SNVs rs1801265 and rs4294451 were quite common (MAF = 0.41-0.47) and in perfect or nearly complete linkage disequilibrium, which might result in reduced risk of fluoropyrimidine-induced toxicity.