From Frequencies to Priorities: Interethnic Distribution of Pharmacogenetic Phenotypes as a Basis for Prioritizing Preemptive Testing in Russia’s Multiethnic Population

Background/Objectives: The frequencies of pharmacogenetically relevant alleles and predicted phenotypes vary substantially between populations, with direct consequences for the expected efficacy and safety of widely prescribed drugs. Russia is one of the most ethnically diverse countries in the world, yet systematic, multi-gene pharmacogenetic data across its ethnic groups, and their implications for targeted implementation of testing, remain limited. This study aimed to characterize the distribution of predicted metabolizer phenotypes for CYP2C9, CYP2C19 and CYP3A5 and of predicted SLCO1B1 transporter function, together with VKORC1 and CYP4F2 genotypes, across 15 ethnic groups of Russia, and to establish the population-level frequency data required for subsequent analysis of regional priorities for pharmacogenetic testing. Methods: A total of 2304 unrelated individuals from 15 ethnic groups were genotyped for CYP2C9*2/*3, CYP2C19*2/*3/*17, CYP3A5*3, SLCO1B1*5, VKORC1 c.-1639G>A, CYP4F2*3, and ABCB1 c.3435C>T. Allele, genotype, and phenotype frequencies were estimated with 95% Wilson confidence intervals. Interethnic differences were assessed using the Fisher exact test (omnibus and pairwise comparisons against the Russian reference group), with the Benjamini–Hochberg false discovery rate correction; composite phenotype categories were further compared using 2 × 2 exact tests. Genotype-based expected warfarin maintenance dose ranges were assigned from CYP2C9 diplotype combined with VKORC1 genotype according to the FDA-approved prescribing information, with CYP4F2*3 carriage considered as a modifying factor. Results: Interethnic variability differed markedly by gene, ranging from minimal for CYP3A5 to pronounced for VKORC1. After correction for multiple comparisons, statistically significant differences from the Russian reference group were identified in up to eight of 14 ethnic groups per gene, affecting CYP2C9-, CYP2C19-, and SLCO1B1-related phenotypes relevant to NSAIDs, clopidogrel, proton pump inhibitors, antidepressants, and statins. The most pronounced pattern was a coordinated shift across CYP2C9 and CYP2C19 in Buryats and Nanais consistent with previously reported East Asian population patterns, alongside an isolated, population-specific extreme in Lezgins, who showed the highest CYP2C9 intermediate/poor metabolizer frequency of all 15 groups. These differences translated into markedly divergent distributions of genotype-based expected warfarin dose ranges, with the lowest range (0.5–2 mg/day) expected in 21.1% of Lezgins, compared with 8.8% overall, and the 3–4 mg/day range predominating in Buryats and Nanais (69.3% and 73.9%). Conclusions: These findings characterize the pharmacogenetic landscape of Russia’s understudied ethnic diversity and provide the population-level frequency data required as one component of any subsequent assessment of where preemptive pharmacogenetic testing should be prioritized–an assessment that additionally requires data on prescribing patterns, clinical outcomes, cost-effectiveness and healthcare infrastructure. The magnitude of the interethnic differences documented here nonetheless indicates that implementation planning guided by population-specific rather than nationally averaged frequencies merits further evaluation in a multiethnic country.