PREVALENCE OF POLYMORPHISMS IN WARFARIN METABOLISMRELATED GENES AMONG THE KAZAKH POPULATION

Abstract

Objective: The study aims to perform a comparative analysis of population frequencies of minor alleles of polymorphisms in the genes CYP2C9 *2 (rs1799853), *3 (rs1057910), *5 (rs28371686), and *6 (rs9332131); CYP2C19 (rs3814637), VKORC1 (rs9934438), CYP4F2 (rs2108622), GGCX (rs11676382), as well as GWAS-associated variants related to resistance to vitamin K antagonists in an ethnically homogeneous Kazakh population, and to assess the distribution and perform a comparative analysis of metabolic phenotypes ("metabolizer types") in comparison with previously studied global populations. Materials and Methods: The research was based on genomic analysis data from 1,900 conditionally healthy individuals of Kazakh ethnicity, obtained within the framework of the 7th Framework Programme of the European Union under Grant Agreement No. 282540. Results: A high frequency of the minor allele of the "Asian" variant rs11676382 in the GGCX gene was identified in the Kazakh population (14.4%) compared to European, East Asian, and South Asian groups. It may indicate a potentially more pronounced impact of this polymorphism on individual warfarin dosing requirements in individuals of Kazakh ethnicity. In the studied Kazakh group, the identified phenotypes and frequencies of metabolizers for CYP2C9 *2 (rs1799853) and *3 (rs1057910) alleles were as follows: 1/1 (80.1%), 1/3 (13.0%), 3/3 (0.25%), 1/2 (6.0%), 2/3 (0.40%), and 2/2 (0.25%). Normal metabolizers (*2 and *3 alleles) comprised 80.1%, intermediate metabolizers - 19.0%, and slow metabolizers - 0.9%. For CYP2C9 *5 (rs28371686) and *6 (rs9332131) alleles, the phenotypes and metabolizer frequencies were: 1/1 (90.0%), 1/6 (6.7%), 1/5 (2.9%), 5/6 (0.3%), and 5/5 (0.1%). Normal metabolizers for *5 and *6 alleles accounted for 90.0%, intermediate - 9.6%, and slow - 0.4%. Conclusion. The results provide additional pharmacogenetic database information for Central Asia, facilitating a better understanding of warfarin pharmacokinetics and pharmacodynamics for individualized warfarin dosing in patients undergoing heart surgery in Kazakhstan.