Русский
Analysis of the frequency of CYP2C9, AGTR1, AGT, ACE, CYP11B2 gene Polymorphisms occurrence in patients with newly diagnosed 1–2 degree arterial hypertension
DOI: https://dx.doi.org/10.18565/pharmateca.2023.14.78-86
E.V. Rebrova, E.V. Shikh, R.E. Kazakov, G.G. Melkonyan, N.P. Kulagina
1) Sechenov University, Moscow, Russia; 2) Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 3) Hospital for War Veterans № 3, Moscow, Russia
Background. The lack of clinical effectiveness of pharmacotherapy for arterial hypertension (AH) may be associated with interindividual genetic variability. The most relevant is the identification of genetic polymorphisms in the genes of key factors regulating the cardiovascular system associated with the functioning of the renin-angiotensin-aldosterone system (RAAS): genes encoding angiotensin-converting enzyme (ACE), angiotensinogen, receptors for angiotensin II type 1, aldosterone synthetase, and also in the gene for the enzyme CYP2C9, one of the main enzymes in the metabolism of angiotensin II receptor blockers (ARBs).
Objective. Determination of the frequency of occurrence of polymorphic variants of the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), AGTR1 (A1166C), AGT (M235T), ACE (I/D polymorphism), CYP11B2 (C-344T) genes and combinations of risk alleles in patients with newly diagnosed 1–2 degree AH followed-up in a Moscow clinic.
Methods. The study included 179 patients with newly diagnosed 1-2 degree AH, 141 (78.8%) women and 38 (21.2%) men aged 32 to 69 years (mean age – 58.2± 6.4 years). In patients with newly diagnosed 1–2 degree AH, permanently residing in Moscow, allelic variants of the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), AGTR1 (A1166C), AGT (M235T), ACE (I/D polymorphism), CYP11B2 (C-344T) genes were analyzed using molecular genetic analysis.
Results: The frequency distribution of genotypes for the CYP2C9*2 gene was as follows: genotype *1*1 was determined in 141 (78.8%) patients, heterozygous genotype for the risk allele *1*2 - in 34 (19%), homozygous *2* 2 – in 4 (2.2%) patients. The distribution of genotypes for the CYP2C9*3 genetic polymorphism was as follows: genotype *1*1 was detected in 146 (81.6%) patients, heterozygous for the nonfunctional allele *1*3 – in 33 (18.4%) patients; patients homozygous for the risk allele of the CYP2C9*3 gene were not identified. The distribution of patient genotypes according to the genetic polymorphism A1166C of the AGTR1 gene is as follows: the AA genotype was determined in 85 (47.5%) patients, the AC genotype in 80 (44.7%) patients, the CC genotype in 14 (7.8%). As a result of molecular genetic analysis of single nucleotide M235T polymorphism of the AGT gene, the following distribution of genotypes was obtained: 36 (20.1%) patients were carriers of the CC genotype, the CT genotype was determined in 98 (54.7%) patients, and the TT genotype was determined in 45 ( 25.1%). According to the data obtained, the carrier frequency of the risk allele D for the I/D polymorphism of the ACE gene was 48.3%, while 45 (25.1%) patients were homozygous for this allele and carriers of the DD genotype, and heterozygous representatives of the ID genotype – 83 (46.4%) patients. The frequency distribution of genotypes for the polymorphism of the aldosterone synthetase gene CYP11B2 (C-344T) was obtained as follows: the CC genotype was determined in 38 (21.2%) patients, the CT genotype in 90 (50.3%) patients and the TT genotype in 51 (28.5%).
Conclusion. There were no statistically significant deviations in the observed frequency of genotypes from the theoretical one determined by the Hardy–Weinberg equilibrium, which indicates this group of patients is in genetic equilibrium and the possibility of extrapolating the study results to the population. In 16.2% of this sample of patients, a combination of risk alleles was determined for all genes studied affecting the pharmacodynamics of RAAS inhibitors, key factors in the regulation of the cardiovascular system. In 6.1% of patients in this sample, carriers of risk alleles for CYP29*2 and pharmacodynamic genes AGT, ACE, CYP11B2 were determined, 4.5% of patients were carriers of risk alleles for CYP2C9*3 and pharmacodynamic genes AGTR1, AGT, ACE, CYP11B2.
Objective. Determination of the frequency of occurrence of polymorphic variants of the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), AGTR1 (A1166C), AGT (M235T), ACE (I/D polymorphism), CYP11B2 (C-344T) genes and combinations of risk alleles in patients with newly diagnosed 1–2 degree AH followed-up in a Moscow clinic.
Methods. The study included 179 patients with newly diagnosed 1-2 degree AH, 141 (78.8%) women and 38 (21.2%) men aged 32 to 69 years (mean age – 58.2± 6.4 years). In patients with newly diagnosed 1–2 degree AH, permanently residing in Moscow, allelic variants of the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), AGTR1 (A1166C), AGT (M235T), ACE (I/D polymorphism), CYP11B2 (C-344T) genes were analyzed using molecular genetic analysis.
Results: The frequency distribution of genotypes for the CYP2C9*2 gene was as follows: genotype *1*1 was determined in 141 (78.8%) patients, heterozygous genotype for the risk allele *1*2 - in 34 (19%), homozygous *2* 2 – in 4 (2.2%) patients. The distribution of genotypes for the CYP2C9*3 genetic polymorphism was as follows: genotype *1*1 was detected in 146 (81.6%) patients, heterozygous for the nonfunctional allele *1*3 – in 33 (18.4%) patients; patients homozygous for the risk allele of the CYP2C9*3 gene were not identified. The distribution of patient genotypes according to the genetic polymorphism A1166C of the AGTR1 gene is as follows: the AA genotype was determined in 85 (47.5%) patients, the AC genotype in 80 (44.7%) patients, the CC genotype in 14 (7.8%). As a result of molecular genetic analysis of single nucleotide M235T polymorphism of the AGT gene, the following distribution of genotypes was obtained: 36 (20.1%) patients were carriers of the CC genotype, the CT genotype was determined in 98 (54.7%) patients, and the TT genotype was determined in 45 ( 25.1%). According to the data obtained, the carrier frequency of the risk allele D for the I/D polymorphism of the ACE gene was 48.3%, while 45 (25.1%) patients were homozygous for this allele and carriers of the DD genotype, and heterozygous representatives of the ID genotype – 83 (46.4%) patients. The frequency distribution of genotypes for the polymorphism of the aldosterone synthetase gene CYP11B2 (C-344T) was obtained as follows: the CC genotype was determined in 38 (21.2%) patients, the CT genotype in 90 (50.3%) patients and the TT genotype in 51 (28.5%).
Conclusion. There were no statistically significant deviations in the observed frequency of genotypes from the theoretical one determined by the Hardy–Weinberg equilibrium, which indicates this group of patients is in genetic equilibrium and the possibility of extrapolating the study results to the population. In 16.2% of this sample of patients, a combination of risk alleles was determined for all genes studied affecting the pharmacodynamics of RAAS inhibitors, key factors in the regulation of the cardiovascular system. In 6.1% of patients in this sample, carriers of risk alleles for CYP29*2 and pharmacodynamic genes AGT, ACE, CYP11B2 were determined, 4.5% of patients were carriers of risk alleles for CYP2C9*3 and pharmacodynamic genes AGTR1, AGT, ACE, CYP11B2.
About the Autors
Corresponding author: Ekaterina V. Rebrova, Cand. Sci. (Med.), Associate Professor, Associate Professor at the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases, Sechenov University, Moscow, Russia; katrina1987@rambler.ru
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