Pharmacogenetic Loci for Rosuvastatin are Associated with Intima-Media Thickness Change and Coronary Artery Disease Risk

Kononov, S. I.; Маль, Г. С.; Azarova, Iuliia; Klyosova, Elena; Bykanova, Marina; Churnosov, Mikhail; Polonikov, Alexey

doi:10.2217/pgs-2021-0097

Cited by 9 publications

(4 citation statements)

References 81 publications

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“…Despite HF is an irreversible progressive disease, the abnormalities in blood lipids (BL), BP, and BG can be identified early and treated effectively with medications. Previous studies have reported that BL, BP, and BG have potential shared genomic loci with HF (7,8). In addition, the present genetics association study of BL, BP, and BG exhibits a substantial sample size, demonstrating significant polygenic heritability and greater multitude of genomic loci in contrast to prior research.…”

Section: Introductioncontrasting

confidence: 53%

Exploring novel risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose: a large-scale multi-trait association analysis

Zhu,

Wang,

Cui

et al. 2023

Preprint

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BackgroundThe comprehensive exploration of genomic risk loci for heart failure (HF) remains constrained, and the genetic role of blood lipids (BL), blood pressure (BP) and blood glucose (BG) in HF has not been fully characterized.MethodsWe first assessed the global and local genetic correlations between HF and the quantitative traits of BL, BP, and BG. We then employed multi-trait association analysis and multi-trait colocalization analysis to identify novel and pleiotropic genomic risk loci for HF. Furthermore, we explored potential genes, pathways, tissues, and cells associated with HF involving BL, BP, and BG. Lastly, we investigated potential therapeutic targets for HF.FindingsWe found extensive global and local genetic correlations between HF and the traits of BL, BP, and BG. Multi-trait association analysis successfully identified 154 novel genomic risk loci for HF. Multi-trait colocalization analysis further revealed 46, 35, and 14 co-localized loci shared by HF with BL, BP, and BG, respectively. We found that the loci shared by HF with these traits rarely overlapped, indicating distinct shared mechanisms. Gene-mapping, gene-based, and transcriptome-wide association analyses prioritized noteworthy candidate genes (such as LPL, GRK5, and TNNC1) for HF. In enrichment analysis, HF exhibited comparable characteristics with cardiovascular traits and metabolic correlated to BL, BP, and BG. We provided genetic evidence for putative drugs, and highlighted 33 robust potential protein targets.InterpretationThese findings will provide biological insights into the pathogenesis for HF, and benefit the development of preventive or therapeutic drugs for HF.

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Section: Introductioncontrasting

confidence: 53%

Exploring novel risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose: a large-scale multi-trait association analysis

Zhu,

Wang,

Cui

et al. 2023

Preprint

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“…The patient cohort comprised 116 Russian patients with the diagnosis of CAD stable angina pectoris grade II-III. The study participants were described in detail in our previous work [31]. Characteristics of the study cohort are given in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…TC levels higher than 4.0 mmol/L and LDL-C levels higher than 1.8 mmol/L were considered criteria for dyslipidemia. Biochemical and ultrasound investigations were described in our previous paper [31]. Plasma lipid levels, except LDL-C, were detected using an automatic laboratory analyzer.…”

Section: Methodsmentioning

confidence: 99%

Lipid-Associated GWAS Loci Predict Antiatherogenic Effects of Rosuvastatin in Patients with Coronary Artery Disease

Kononov¹,

Azarova²,

Klyosova³

et al. 2023

Preprint

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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&lt;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&lt;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.

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“…DNA samples were obtained from the biobank of Research Institute for Genetic and Molecular Epidemiology of Kursk State Medical University. The samples were collected previously in the frames of genetic studies of cardiovascular and other chronic diseases for the period from 2003 to 2018 [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. A total number of participants comprises 1700 unrelated individuals of Slavic origin, inhabitants of the Kursk region, and included 991 patients with a diagnosis of coronary artery disease (633 men and 358 women, medium age 59.9 ± 8.8 years) who were hospitalized in Cardiology Divisions of Kursk Emergency Hospital and Vascular Surgery Division of Regional Clinical Hospital (Kursk).…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease

et al. 2022

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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.

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Pharmacogenetic Loci for Rosuvastatin are Associated with Intima-Media Thickness Change and Coronary Artery Disease Risk

Cited by 9 publications

References 81 publications

Exploring novel risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose: a large-scale multi-trait association analysis

Exploring novel risk loci for heart failure and the shared genetic etiology with blood lipids, blood pressure, and blood glucose: a large-scale multi-trait association analysis

Lipid-Associated GWAS Loci Predict Antiatherogenic Effects of Rosuvastatin in Patients with Coronary Artery Disease

Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease

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