Станислав Игоревич Кононов

Aim. To study the effect of EDNRA rs6842241 and MRAS rs9818870 polymorphic variants on the lipid-lowering effect of rosuvastatin in patients with coronary artery disease (CAD), and to determine the role of these loci in the development of CAD among Central Russia residents.Material and methods. The pharmacogenetic study involved 116 patients with class II-III stable angina. Patients received rosuvastatin with dose titration to achieve target low-density lipoprotein cholesterol (LDL-C) levels. The genetic and epidemiological study included DNA samples of 1960 Central Russia residents (1261 patients with CAD and 699 healthy individuals). Genotyping of polymorphic variants was performed on a MassARRAY-4 genomic mass spectrometer. Associations of polymorphisms with lipid changes for 1, 6 and 12 months of follow-up were calculated using linear regression analysis adjusted for sex, age, body mass index and rosuvastatin dose; associations with CAD risk — using logistic regression analysis adjusted for sex and age. The statistical significance of associations was calculated using the permutation test.Results. Carriage of the AA and CA genotypes of EDNRA rs6842241 variant was associated with a weakening of the rosuvastatin lipid-lowering effect in relation to total cholesterol (β=0,075, p=0,001) and LDL-C (β=0,145, p=0,017) at the end of the first month and 12 months of therapy (β=0,049, p=0,013 and β=0,072, p=0,040, respectively). Carriage of the AA genotype of EDNRA rs6842241 variant was associated with an increased CAD risk (odds ratio 5,36; 95% confidence interval 1,62-17,71, p=0,004). MRAS rs9818870 variant was not associated with rosuvastatin pharmacogenetics or with the CAD risk. Both polymorphic variants were not associated with lipid levels outside of lipid-lowering therapy, as well as with the triglyceride changes. High-density lipoprotein cholesterol levels during the entire follow-up period changed insignificantly.Conclusion. The EDNRA rs6842241 variant is associated with both a weakening of the lipid-lowering effect of rosuvastatin in CAD and an increased risk of its development in the population.

Aim   To study the relationship of single nucleotide polymorphisms rs2681472 and rs17249754 in the ATP2B1 gene with risk of ischemic heart disease (IHD) and arterial hypertension (AH) among residents of Central Russia and to evaluate the trigger role of smoking as a risk factor for development of IHD and AH in carriers of ATP2B1 gene polymorphic variants. Material and methods   The study included DNA samples from 1960 residents of Central Russia of Slavic origin. Among them, there were 1261 patients with cardiovascular diseases and 699 healthy persons. The vast majority of patients had both IHD and AH. Genotyping was performed using the iPLEX technique on a MassARRAY-4 genomic mass-spectrometer. The relationship of ATP2B1 alleles, genotypes, and haplotypes with the risk of diseases was calculated by logistic regression analysis with adjustments for sex and age. Results   Carriage of AG and GG (rs2681472) genotypes and GA (rs17249754) genotype was associated with a reduced risk of both IHD (p=0.0057 and p=0.022 for rs2681472 and rs17249754, respectively) and AH (p=0.016 and p=0.036, respectively). Rare rs2681472G-rs17249754G and rs2681472A-rs17249754A haplotypes were associated with a reduced risk of IHD (odds ratio, OR, 0.22; 95 % CI: 0.11–0.46, p=0.0001) and AH (OR, 0.22; 95 % CI: 0.10–0.47, p=0.0001). Analysis of the groups stratified by the smoking status showed that in smokers, the studied polymorphic variants did not have a protective action with respect of either IHD or AH. However, in non-smokers, the genotypes AG and GG rs2681472 (OR, 0.62; 95 % CI: 0.47–0.80, p=0.0004) and GA rs17249754 (OR, 0.61; 95 % CI: 0.47–0.81, p=0.0004) were associated with a reduced risk of IHD and AH (OR, 0.63; 95 % CI: 0.48–0.83, p=0.0004 for rs2681472; OR, 0.63; 95 % CI: 0.48–0.83, p=0.001 for rs17249754), as well as the carriage of the minor alleles rs2681472‑G and rs17249754‑A. Conclusion   It was shown for the first time that the polymorphic variants rs17249754 and rs2681472 of the ATP2B1 gene are associated with a reduced risk for IHD and AH only in non-smokers.

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and p-values were calculated through adaptive permutation tests by the PLINK software, v1.9. Over one-year rosuvastatin therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm < 0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm < 0.05). In conclusion, polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and P-values were calculated through adaptive permutation tests. Over one-year therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm<0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm<0.05). In conclusion, the polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.

The study was designed to evaluate putative mechanisms by which lipid-associated loci identified by genome-wide association studies (GWAS) are involved in the molecular pathogenesis of coronary artery disease (CAD) using a comprehensive statistical and bioinformatics analysis. A total of 1700 unrelated individuals of Slavic origin from the Central Russia, including 991 CAD patients and 709 healthy controls were examined. Sixteen lipid-associated GWAS loci were selected from European studies and genotyped using the MassArray-4 system. The polymorphisms were associated with plasma lipids such as total cholesterol (rs12328675, rs4846914, rs55730499, and rs838880), LDL-cholesterol (rs3764261, rs55730499, rs1689800, and rs838880), HDL-cholesterol (rs3764261) as well as carotid intima-media thickness/CIMT (rs12328675, rs11220463, and rs1689800). Polymorphisms such as rs4420638 of APOC1 (p = 0.009), rs55730499 of LPA (p = 0.0007), rs3136441 of F2 (p < 0.0001), and rs6065906 of PLTP (p = 0.002) showed significant associations with the risk of CAD, regardless of sex, age, and body mass index. A majority of the observed associations were successfully replicated in large independent cohorts. Bioinformatics analysis allowed establishing (1) phenotype-specific and shared epistatic gene–gene and gene–smoking interactions contributing to all studied cardiovascular phenotypes; (2) lipid-associated GWAS loci might be allele-specific binding sites for transcription factors from gene regulatory networks controlling multifaceted molecular mechanisms of atherosclerosis.

Aim: Polymorphisms at LPA, LDLR, APOE, APOC1, MYLIP and ABCG2 are attractive targets for assessment of their impact on lipid-lowering therapy with rosuvastatin. The present study investigated wheth... Graphical abstract

Полиморфные варианты гена аполипопротеина E: связь с риском развития ишемической болезни сердца и эффективностью гиполипидемической терапии розувастатином

Полиморфные варианты гена аполипопротеина E: связь с риском развития ишемической болезни сердца и эффективностью гиполипидемической терапии розувастатином