Population impact of pharmacogenetic tests in admixed populations across the Americas

The current population of the Americas (~1 billion people) is highly heterogeneous as a result of five centuries of admixture between three major parental populations, namely Native Amerindians, Europeans, and subSaharan Africans. This heterogeneity has important pharmacogenetic (PGx) implications. The present study explores this issue with respect to the population impact of PGx tests listed in the CPIC and DWPG guidelines for the cancer chemotherapeutic agents fluoropyrimidines, irinotecan, and thiopurines. Population impact was assessed by the number of individuals needed to genotype (NNG) and to treat [NNT] in order to prevent one additional adverse effect. The 1000 Genomes Project database was accessed to obtain genotypes for the relevant PGx markers and to estimate individual proportions of Native, European, and African ancestry for six recently admixed populations across the Americas. The ancestry proportions were then employed to devise three sub-cohorts, denoted NAT, EUR, and AFR, in which one of the three major ancestral roots predominates largely (8 to 30-fold) over the other two. Minor allele frequency (MAF) of NUDT15 rs116855232, TPMT rs1800460, and UGT1A1 rs887829 differed significantly across the three sub-cohorts, whereas no difference was observed for TPMT rs1142345 and 1800462, and the four DPYD variants interrogated. The frequency of combined TPMT/NUDT and UGT1A1, but not DPD, metabolic phenotypes differed significantly among the sub-cohorts. The NNGs for the drug/sub-cohorts pairs, ranged from 12 (irinotecan/UGT1A1 in EUR) to 360 (fluoropyrimidines/DPYD in NAT). Differences in MAF of the interrogated variants and consequently in the distribution of metabolic phenotypes, plus the variable individual proportions of biogeographical ancestry concur to the 30-fold range of NNGs for the PGx tests, across the sub-cohorts. This large variation is likely to influence the perceived benefits and the clinical adoption of PGx screening for the chemotherapeutic agents investigated. This is of especial concern for fluoropyrimidines, in view of the large NNGs observed in the study sub-cohorts (NNG = 176-360) and confirmed in cancer patients from Brazil (NNG = 312).