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Genome-wide association studies of coronary artery disease and heart failure: where are we going?

ABSTRACT: The heart diseases that account for a large amount of morbidity and mortality in the developed world (coronary artery disease, myocardial infarction and heart failure) are phenotypically heterogeneous disorders. It has been suspected for many years that genetics may have an important role in these diseases and their poor outcome. However, their complex and likely polygenic pathophysiology has confounded clear understanding of the genetic contribution to their etiology. Despite technological progress and great promise associated with genome-wide association studies, to date the results of their application to coronary artery disease, myocardial infarction and heart failure have yielded limited insights into these common diseases. This review discusses the current status of genome-wide association studies as they have been applied to these cohorts. The potential limitations of these studies, as well as potential future directions for identifying important genes are also discussed.

SUBMITTER: Dorn GW

PROVIDER: S-EPMC3428120 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association studies of coronary artery disease and heart failure: where are we going?

Dorn Gerald W GW Cresci Sharon S

Pharmacogenomics 20090201 2

The heart diseases that account for a large amount of morbidity and mortality in the developed world (coronary artery disease, myocardial infarction and heart failure) are phenotypically heterogeneous disorders. It has been suspected for many years that genetics may have an important role in these diseases and their poor outcome. However, their complex and likely polygenic pathophysiology has confounded clear understanding of the genetic contribution to their etiology. Despite technological prog ...[more]

PMID: 19207022

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Project description:Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD.Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (http://www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatic modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype-phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD.Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05).We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies.

Project description:AimsCoronary artery disease (CAD) is a common cause of heart failure (HF). It remains unclear who, when and why to direct towards coronary revascularization. The outcomes of coronary revascularization in HF patients are still a matter of debate nowadays. This study aims to evaluate the effect of revascularization strategy on all-cause of death in the context of ischaemic HF.Methods and resultsAn observational cohort was conducted on 692 consecutive patients who underwent coronary angiography at the University Hospital of Toulouse between January 2018 and December 2021 for either a recent diagnosis of HF or a decompensated chronic HF, and in whom coronary angiograms showed at least 50% obstructive coronary lesion. The study population was divided into two groups according to the performance or not of a coronary revascularization procedure. The living status (alive or dead) of each of the study's participants was observed by April 2022. Seventy-three per cent of the study population underwent coronary revascularization either by percutaneous coronary intervention (66.6%) or coronary artery bypass grafting (6.2%). Baseline characteristics including age, sex and cardiovascular risk factors did not differ between the invasive and conservative groups, respectively. Death occurred in 162 study participants resulting in an all-cause mortality rate of 23.5%; 26.7% of observed deaths have occurred in the conservative group versus 22.2% in the invasive group (P = 0.208). No difference in survival outcomes has been observed over a mean follow-up period of 2.5 years (P = 0.140) even after stratification by HF categories (P = 0.132) or revascularization modalities (P = 0.366).ConclusionsFindings from the present study showed comparable all-cause mortality rates between groups. Coronary revascularization does not modify short-term survival outcomes in HF patients compared with optimal medical therapy alone outside the setting of acute coronary syndrome.

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Genome-wide association studies of coronary artery disease and heart failure: where are we going?

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Genome-wide association studies of coronary artery disease and heart failure: where are we going?

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