Population Genomics Insights into Pharmacogenomic Differentiation Between East Asians and Europeans

Genetic variation contributes substantially to interindividual and interpopulation differences in drug response, yet most pharmacogenomic studies remain biased toward European populations. Here, we systematically assessed pharmacogenomic variation across East Asians (EAS) and Europeans (EUR) using public genomic datasets and investigated the potential evolutionary forces shaping these differences. Our analyses revealed that EAS populations generally harbor a lower frequency of pharmacogenomic variants previously associated with reduced drug response compared with EUR populations, indicating population-level differences in the distribution of PGx variants. Drug-associated genes exhibited threefold higher population differentiation than the genome-wide background (F_ST = 0.18 vs. 0.06). Key transport genes such as SLCO1B3/SLCO1B7 showed striking differences in cumulative allele probability (EAS: 18.69% vs. EUR: 91.60%), suggesting population-level divergence in drug transport and pharmacokinetics. Population genetic analyses revealed stronger signals of positive selection on PGx variants in EAS populations, likely reflecting historical adaptations to pathogen and dietary pressures. For instance, the VKORC1-rs9923231-T allele, which enhances warfarin sensitivity, shows evidence of selection in EAS populations (XP-EHH = 3.58) and may relate to vitamin K intake. Conversely, the EUR-enriched SH2B3-rs3184504-T allele (AF_EUR: 0.46 vs. AF_EAS: 0.003) has been associated with selection related to blood pressure regulation. Collectively, these findings highlight the importance of incorporating population diversity into pharmacogenomic research and underscore the potential need for population-specific drug response guidelines to advance global precision medicine.