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A comprehensive linkage analysis for myocardial infarction and its related risk factors
Ulrich Broeckel1, Christian Hengstenberg, Björn Mayer
1Department of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Insights
A genome-wide scan identified a key genetic region on chromosome 14 linked to myocardial infarction (MI) risk. This finding suggests new susceptibility genes contributing to coronary artery disease, beyond known risk factors.
Area of Science:
- Cardiovascular Genetics
- Human Genetics
- Disease Genomics
Background:
- Coronary artery disease (CAD) and myocardial infarction (MI) are leading global causes of mortality.
- Established risk factors include diabetes mellitus, arterial hypertension, and hypercholesterolemia.
- A positive family history indicates additional, yet unidentified, genetic susceptibility factors for CAD and MI.
Purpose of the Study:
- To conduct a whole-genome scan in families to identify chromosomal regions associated with MI and its genetic risk factors.
- To pinpoint specific genetic loci contributing to the heritability of myocardial infarction.
- To investigate the genetic linkage of known CAD risk factors to specific chromosomal regions.
Main Methods:
- Variance component analysis was applied to genome-wide data from 513 families.
- Genetic linkage analysis was performed incorporating established cardiovascular risk factors.
- Statistical methods included calculating lod scores to assess linkage significance (pointwise and genome-wide).
Main Results:
- A significant principal locus for myocardial infarction risk was identified on chromosome 14 (lod score 3.9).
- Serum lipoprotein (a) concentrations showed linkage to the apolipoprotein (a) locus and a novel locus on chromosome 1.
- Suggestive linkage was found for diabetes mellitus (chromosome 6), hypertension (chromosomes 1 and 6), cholesterol levels (chromosomes 1 and 17), and triglycerides (chromosome 9).
Conclusions:
- A novel major genetic locus on chromosome 14 significantly contributes to myocardial infarction susceptibility.
- The identified MI locus on chromosome 14 does not overlap with loci linked to the analyzed risk factors.
- This study provides evidence for new genetic determinants of CAD and MI, distinct from previously known risk factor associations.
Abstract:
Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.