Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

AbstractDrug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target’s expression or function, as a tool to anticipate the effect of drug action on the same target. Here we apply MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with blood lipids (HDL-C, LDL-C and triglycerides), we robustly prioritize 30 targets that might elicit beneficial effects in the prevention or treatment of CHD, including NPC1L1 and PCSK9, the targets of drugs used in CHD prevention. We discuss how this approach can be generalized to other targets, disease biomarkers and endpoints to help prioritize and validate targets during the drug development process.

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Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

10.21203/rs.3.rs-122651/v1 ◽

2021 ◽

Author(s):

Maria Gordillo-Maranon ◽

Magdalena Zwierzyna ◽

Pimphen Charoen ◽

Fotios Drenos ◽

Sandesh Chopade ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Drug Target ◽

Drug Targets ◽

Human Genetics ◽

Expression Profiles ◽

Gene Encoding ◽

Human Protein Atlas ◽

Dna Sequence Variants ◽

Protein Expression Profiles

Abstract Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter its expression or function, as a tool to anticipate the effect of drug action on the same target. Here, we applied MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets were further prioritized using genetic co-localization, protein expression profiles from the Human Protein Atlas and, for targets with a licensed drug or an agent in clinical development, by sourcing data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with circulating blood lipids (HDL-C, LDL-C and triglycerides), we were able to robustly prioritize 30 targets that might elicit beneficial treatment effects in the prevention or treatment of CHD. The prioritized list included NPC1L1 and PCSK9, the targets of licensed drugs whose efficacy has been already proven in clinical trials. To conclude, we discuss how this approach can be generalized to other targets, disease biomarkers and clinical end-points to help prioritize and validate targets during the drug development process.

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Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

10.1101/2020.11.11.377747 ◽

2020 ◽

Author(s):

María Gordillo-Marañón ◽

Magdalena Zwierzyna ◽

Pimphen Charoen ◽

Fotios Drenos ◽

Sandesh Chopade ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Disease Prevention ◽

Drug Target ◽

Drug Targets ◽

Human Genetics ◽

Mendelian Randomization ◽

Expression Profiles ◽

Coronary Heart Disease Prevention ◽

Heart Disease Prevention

AbstractDrug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter its expression or function, as a tool to anticipate the effect of drug action on the same target. Here, we applied MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets were further prioritized using genetic co-localization, protein expression profiles from the Human Protein Atlas and, for targets with a licensed drug or an agent in clinical development, by sourcing data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with circulating blood lipids (HDL-C, LDL-C and triglycerides), we were able to robustly prioritize 30 targets that might elicit beneficial treatment effects in the prevention or treatment of CHD. The prioritized list included NPC1L1 and PCSK9, the targets of licensed drugs whose efficacy has been already proven in clinical trials. To conclude, we discuss how this approach can be generalized to other targets, disease biomarkers and clinical end-points to help prioritize and validate targets during the drug development process.One Sentence SummaryWe provide genetic support for lipid-modifying drug targets for coronary heart disease prevention using drug target Mendelian randomization and further prioritization based on clinical and biological evidence.

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Drug Target Prediction Based on the Herbs Components: The Study on the Multitargets Pharmacological Mechanism of Qishenkeli Acting on the Coronary Heart Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/698531 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 20

Author(s):

Yong Wang ◽

Zhongyang Liu ◽

Chun Li ◽

Dong Li ◽

Yulin Ouyang ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Angiotensin Ii ◽

Drug Target ◽

Drug Targets ◽

Target Prediction ◽

Coronary Artery Ligation ◽

Potential Drug ◽

Drug Target Prediction ◽

Potential Drug Targets

In this paper, we present a case study of Qishenkeli (QSKL) to research TCM’s underlying molecular mechanism, based on drug target prediction and analyses of TCM chemical components and following experimental validation. First, after determining the compositive compounds of QSKL, we use drugCIPHER-CS to predict their potential drug targets. These potential targets are significantly enriched with known cardiovascular disease-related drug targets. Then we find these potential drug targets are significantly enriched in the biological processes of neuroactive ligand-receptor interaction, aminoacyl-tRNA biosynthesis, calcium signaling pathway, glycine, serine and threonine metabolism, and renin-angiotensin system (RAAS), and so on. Then, animal model of coronary heart disease (CHD) induced by left anterior descending coronary artery ligation is applied to validate predicted pathway. RAAS pathway is selected as an example, and the results show that QSKL has effect on both rennin and angiotensin II receptor (AT1R), which eventually down regulates the angiotensin II (AngII). Bioinformatics combing with experiment verification can provide a credible and objective method to understand the complicated multitargets mechanism for Chinese herbal formula.

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Exploring pharmacological mechanisms of Xueshuan-Xinmai-Ning tablets acting on coronary heart disease based on drug target-disease gene interaction network

Phytomedicine ◽

10.1016/j.phymed.2018.09.018 ◽

2019 ◽

Vol 54 ◽

pp. 159-168 ◽

Cited By ~ 7

Author(s):

Xia Mao ◽

Haiyu Xu ◽

Sen Li ◽

Jin Su ◽

Weijie Li ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Drug Target ◽

Disease Gene ◽

Interaction Network ◽

Gene Interaction ◽

Gene Interaction Network ◽

Target Disease

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A new approach to the treatment of dyslipidemia

Medicina ◽

10.3390/medicina44050053 ◽

2008 ◽

Vol 44 (5) ◽

pp. 407 ◽

Cited By ~ 4

Author(s):

Sigita Kėvelaitienė ◽

Rimvydas Šlapikas

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Cardiovascular Diseases ◽

High Risk ◽

Statin Therapy ◽

Cholesterol Absorption ◽

Diabetic Patients ◽

Intestinal Cholesterol Absorption ◽

Beneficial Effects ◽

European Society Of Cardiology

During the last decade, the evidence of beneficial effects of cholesterol lowering in patients with coronary heart disease has been proven in many clinical trials. The National Cholesterol Education Program (NCEP) released 2004 update to the Adult Treatment Panel III (ATP III) guidelines. The new guidelines of European Society of Cardiology announced in 2007 support more intensive LDL-C lowering in patients at high risk of cardiovascular diseases. For patients at the highest risk of cardiovascular diseases (diabetic patients with coronary heart disease), the recommended LDL-C goal is <1.8 mmol/L. In very high-, high-, and moderately high-risk patients, statin therapy should be considered with a treatment targeting an LDL-C reduction of 30– 40%. Clinical studies have shown that statin therapy alone is not always effective, especially in patients with primary hypercholesterolemia. Furthermore, high doses of statins can increase the possibility of adverse events. The combination of statins with intestinal cholesterol absorption inhibitors is more effective than statin monotherapy in LDL-C lowering and is well tolerated.

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Circular RNA expression profiles and bioinformatic analysis in coronary heart disease

Epigenomics ◽

10.2217/epi-2019-0369 ◽

2020 ◽

Vol 12 (5) ◽

pp. 439-454 ◽

Cited By ~ 2

Author(s):

Fangpu Yu ◽

Yuanyuan Tie ◽

Ya Zhang ◽

Zunzhe Wang ◽

Liwen Yu ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Coronary Arteries ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Expression Profiles ◽

Peripheral Blood Mononuclear ◽

Qrt Pcr ◽

Blood Mononuclear Cells

Aim: We aimed to identify the expression profile and role of circular RNAs (circRNAs) in coronary heart disease (CHD). Materials & methods: We performed sequence analysis of circRNAs in peripheral blood mononuclear cells of 70 CHD patients and 30 controls. Eight selected circRNAs were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in human atherosclerotic coronary arteries. Results: In total, 2283 downregulated and 85 upregulated circRNAs were identified in CHD. Parental genes of top 100 dysregulated-circRNAs are related to metabolism and protein modification, and 12 circRNAs might upregulate their CHD-related parental genes through miRNA sponges. Of the eight circRNAs validated in atherosclerotic coronary arteries by qRT-PCR, six were consistent with sequencing results of peripheral blood mononuclear cells. Conclusion: As potential ceRNAs, dysregulated circRNAs may be involved in CHD pathophysiology.

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The Controversial Role of Irisin in Clinical Management of Coronary Heart Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.678309 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wen-Lu Ou-Yang ◽

Bei Guo ◽

Feng Xu ◽

Xiao Lin ◽

Fu-Xing-Zi Li ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Clinical Management ◽

Gene Knockout ◽

Cellular Mechanisms ◽

Beneficial Effects ◽

Glucose And Lipid Metabolism ◽

Metabolic Functions ◽

Gene Knockout Mice

Irisin, a PGC1α-dependent myokine, was once believed to have beneficial effects induced by exercise. Since its first discovery of adipose browning in 2012, multiple studies have been trying to explore the metabolic functions of irisin, such as glucose and lipid metabolism. However, recently many studies with irisin concentration measuring were doubt for methodological problems, which may account for the continuous inconsistencies. New tools like recombinant irisin and gene-knockout mice are required to reconfirm the questioned functions of irisin. In this paper, we make a critical introduction to the latest researches concerning the relationship between irisin and coronary heart disease, which includes atherosclerosis, stable angina pectoris and acute coronary syndromes. These studies provided various controversial evidence of short and long-term monitoring and therapeutic effect from molecular cellular mechanisms, in vivo experiments and epidemiological investigation. But with ambiguities, irisin still has a long way to go to identify its functions in the clinical management.

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LDL-C/HDL-C and carotid plaques in patients with coronary heart disease: A Chinese cohort study

10.21203/rs.3.rs-800910/v1 ◽

2021 ◽

Author(s):

Zhu Li ◽

Qi Cheng ◽

Yijia Liu ◽

Xufeng Cheng ◽

Shuo Wang ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Large Scale ◽

Healthy Lifestyle ◽

Density Lipoprotein ◽

Estimating Equation ◽

Carotid Plaques ◽

Cholesterol Ratio ◽

Beneficial Effects ◽

High Level

Abstract Background: Evidence of the association the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) with the carotid plaques remains limited. The purpose of this study is to examine the association between LDL-C/HDL-C and carotid plaques of coronary heart disease (CHD), and to study what extent a healthy lifestyle reduces the risk of carotid plaques.Methods: In this large-scale and multi-center retrospective study, a total of 9,426 participants to explore the association between LDL-C/HDL-C and carotid plaques. No smoking and no drinking were considered healthy lifestyle. Generalised estimating equation models and conditional logistic regressions were used in statistical analyses.Results: In all the 9,426 participants, there were 6,989 (74.15%) patients having identified carotid plaques. High levels of LDL-C/HDL-C had a higher risk of carotid plaques than other lipid variables (OR:1.63; 95%CI:1.43-1.86). In stratified analyses by LDL-C/HDL-C triplet, participants in the LDL-C/HDL-C (＞3mmol/L) group had a higher risk of carotid plaques compared to other two groups. Compared with the unfavourable lifestyle, intermediate lifestyle or favourable lifestyle was associated with a significant 30% or 67% decrease in carotid plaques risk among patients with the LDL-C/HDL-C(＞3mmol/L) respectively. There were significantly additive and multiplicative interactions between lifestyle and LDL-C/HDL-C on carotid plaques.Conclusion: Our findings provide evidence that a high level of LDL-C/HDL-C can increase the risk of carotid plaques in patients with CHD. And adhering to a healthy lifestyle has additive beneficial effects on reducing the risk of carotid plaques.

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