Prevalence of CYP3A4*22 (rs35599367) C>T and CYP3A5*3 (rs776746) A>G gene polymorphisms among Yakuts and Russians with drug-resistant pulmonary tuberculosis

Background. Treatment of drug-resistant tuberculosis is associated with numerous medical and societal problems; therefore, the search continues for

measures to improve treatment outcomes through the development of new drugs and chemotherapy regimens. Bedaquiline metabolized by the cytochrome P450 isoenzyme CYP3A4. CYP3A4 and CYP3A5 polymorphisms can lead to variability in bedaquiline plasma concentrations, which in turn affects treatment efficacy and safety. Currently, there are no data on the prevalence of CYP3A4*22 and CYP3A5*3 gene polymorphic variants among Yakuts and Russians with tuberculosis.

Objective. To study the carrier frequency of CYP3A4*22 (rs35599367) C>T and CYP3A5*3 (rs776746) A>G gene polymorphisms among Yakuts and Russians with drug-resistant tuberculosis compared to the normal variability of the studied gene allelic variants in East Asian and European populations.

Methods. A cross-sectional comprehensive study was conducted on 255 patients of Yakut and Russian ethnicity with drug-resistant pulmonary tuberculosis. CYP3A4*22 (rs35599367) C>T and CYP3A5*3 (rs776746) A>G polymorphisms were determined by real-time polymerase chain reaction. For comparative analysis, data on the carrier frequency of CYP3A4*22 and CYP3A5*3 allelic variants in East Asian and European populations were used.

Results. In patients with drug-resistant pulmonary tuberculosis, the frequency of the T allele of the CYP3A4*22 gene was significantly lower in the Siberian group compared to the frequency in the Eurasian group (p = 0.003). The wild-type genotype (CC) CYP3A4*22 was significantly more common in the Siberian group of patients than in the Eurasian group, whereas the heterozygous genotype (CT) was less represented in the Siberian population (p = 0.003). The AA genotype of CYP3A5*3 was less common in the Siberian group relative to its frequency in the Eurasian group (p = 0.021), the heterozygous AG genotype was much less frequently detected in the Siberian population of patients (p < 0.001), and the GG genotype predominated in the Siberian group and was less frequently determined in the Eurasian population (p < 0.001). The frequencies of alleles and genotypes of the CYP3A5*3 gene in patients with drug-resistant pulmonary tuberculosis did not differ between the Yakut and Russian populations. The distribution of CYP3A5*3 alleles and genotypes in the Russian population was the same as in the general European profile (p > 0.05). Differences were found between Yakuts and East Asians for all analyzed parameters (p < 0.05).

Conclusion. Features of the distribution of CYP3A4*22 and CYP3A5*3 gene allelic variants affect the rate of drug metabolism among patients of Yakut

and Russian ethnicity. Differences in allelic variants and genotypes of CYP3A4 and CYP3A5 in Russian and Yakut populations with drug-resistant pulmonary tuberculosis can significantly modify clinical efficacy and the development of adverse reactions during bedaquiline treatment, as the CYP3A isoenzyme of cytochrome P450 plays a primary role in its oxidation.

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