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Genetic causes of myocardial infarction: new insights from genome-wide association studies.

ABSTRACT: BACKGROUND: A positive family history for myocardial infarction (MI) is known to be a major cardiovascular risk factor. The current European guidelines therefore recommend intensified primary prevention for the siblings and children of persons who have had an MI. Although the genes underlying the heritable component of MI were largely unknown previously, the development of new molecular genetic methods, and particularly the advent of genome-wide association (GWA) studies, has led to the discovery of numerous genetic variants that are associated with an elevated risk of MI. METHODS: In this article, we review GWA studies on MI and coronary heart disease (CHD) that were retrieved by a selective literature search from 2007 onward. We comment on their implications for clinical practice. RESULTS: In the last three years, GWA studies have enabled the identification of many alleles that confer a higher risk of MI. A total of eleven chromosomal regions have been replicated and associated with the disease, and their functional significance has been studied. Furthermore, it has been shown that some of the manifestations of CHD, e.g., calcification, ectasia and main-stem stenosis, are more strongly inherited than others. CONCLUSION: The results of recent GWA studies for MI and CHD will aid in individual risk prediction for MI by molecular biological means. They will also permit the development of new approaches to research on the pathophysiology of myocardial infarction.

SUBMITTER: Erdmann J

PROVIDER: S-EPMC2965371 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Genetic causes of myocardial infarction: new insights from genome-wide association studies.

Erdmann Jeanette J Linsel-Nitschke Patrick P Schunkert Heribert H

Deutsches Arzteblatt international 20101008 40

<h4>Background</h4>A positive family history for myocardial infarction (MI) is known to be a major cardiovascular risk factor. The current European guidelines therefore recommend intensified primary prevention for the siblings and children of persons who have had an MI. Although the genes underlying the heritable component of MI were largely unknown previously, the development of new molecular genetic methods, and particularly the advent of genome-wide association (GWA) studies, has led to the d ...[more]

PMID: 21031128

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Project description:ObjectivesIdentification of patient subpopulations susceptible to develop myocardial infarction (MI) or, conversely, those displaying either intrinsic cardioprotective phenotypes or highly responsive to protective interventions remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with perioperative MI in patients undergoing coronary artery bypass grafting using genome-wide association methodology.Setting107 secondary and tertiary cardiac surgery centres across the USA.ParticipantsWe conducted a stage I genome-wide association study (GWAS) in 1433 ethnically diverse patients of both genders (112 cases/1321 controls) from the Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMAGIC) study, and a stage II analysis in an expanded population of 2055 patients (225 cases/1830 controls) combined from the GeneMAGIC and Duke Perioperative Genetics and Safety Outcomes (PEGASUS) studies. Patients undergoing primary non-emergent coronary bypass grafting were included.Primary and secondary outcome measuresThe primary outcome variable was perioperative MI, defined as creatine kinase MB isoenzyme (CK-MB) values ≥10× upper limit of normal during the first postoperative day, and not attributable to preoperative MI. Secondary outcomes included postoperative CK-MB as a quantitative trait, or a dichotomised phenotype based on extreme quartiles of the CK-MB distribution.ResultsFollowing quality control and adjustment for clinical covariates, we identified 521 single nucleotide polymorphisms in the stage I GWAS analysis. Among these, 8 common variants in 3 genes or intergenic regions met p<10(-5) in stage II. A secondary analysis using CK-MB as a quantitative trait (minimum p=1.26×10(-3) for rs609418), or a dichotomised phenotype based on extreme CK-MB values (minimum p=7.72×10(-6) for rs4834703) supported these findings. Pathway analysis revealed that genes harbouring top-scoring variants cluster in pathways of biological relevance to extracellular matrix remodelling, endoplasmic reticulum-to-Golgi transport and inflammation.ConclusionsUsing a two-stage GWAS and pathway analysis, we identified and prioritised several potential susceptibility loci for perioperative MI.

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Genetic causes of myocardial infarction: new insights from genome-wide association studies.

Publications

Genetic causes of myocardial infarction: new insights from genome-wide association studies.

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