Allelic variants of CYP2C9, CYP2C19, CYP2D6 cytochromes in the Russian population: Prevalence and regional distribution

Introduction. Determination of the CYP2C9, CYP2C19, and CYP2D6 genotypes enables therapy personalization for a wide range of medications. The currently available diagnostic panels and international guidelines governing the scope of testing are based on global data concerning the allelic polymorphism of these genes.

Objective. To determine the distribution of allelic variants of the CYP2C9, CYP2C19, and CYP2D6 genes in the population of the Russian Federation, taking regional characteristics into account.

Materials and methods. The study was conducted on a sample from the Genetic Database (GDB) of the Centre for Strategic Planning and Management of Biomedical Health Risks (n = 121,442, covering 85 Russian federal subjects). Whole-genome DNA sequencing was performed for all participants, with CYP2C9, CYP2C19, and CYP2D6 genotyping determined using the PAnno software. In regions with a sufficient number of observations, variant frequencies and the proportions of different metabolic phenotypes were compared, identifying high-risk regions and those with an allelic structure differing from the overall population.

Results. The prevalence of impaired metabolism for CYP2C9 substrates in the population is estimated at 33.66%, for CYP2C19 at 25.37%, and for CYP2D6 at 8.29%. The prevalence of accelerated metabolism for CYP2C19 substrates is 37.37%. The following regions are identified as high-risk for the presence of impaired metabolism of substrates for at least one of the studied isoenzymes: the Republics of Chechnya, Dagestan, Ingushetia, Kabardino-Balkaria, North Ossetia, Chuvashia, Mari El, Udmurtia, Tatarstan, Tyva, Sakha (Yakutia), Kalmykia, Buryatia, Karelia, as well as Rostov Oblast, Sakhalin Oblast, Irkutsk Oblast, and Novosibirsk Oblast. This risk manifests due to both quantitative differences in the frequency of common allelic variants and the presence of rare alleles in specific regions, such as CYP2C9*29, CYP2C9*12, CYP2C19*8, CYP2D6*32, and CYP2D6*7.

Conclusions. The obtained results provide the basis for the development of domestic diagnostic panels and for implementing a differentiated approach to pharmacogenetic testing across various biogeographic groups within the country. The introduction of such panels must be accompanied by health economic evaluation for each drug whose effectiveness and safety depends substantially on the CYP2C9, CYP2C19, and CYP2D6 genotype.

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