A comprehensive linkage analysis for myocardial infarction and its related risk factors

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.

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

“…This concept is attractive, since it addresses platelet hyperreactivity super-imposed to coronary atherosclerosis to act as the final mechanism which translates risk factor-dependent vessel wall morphology into blood-dependent thrombotic infarction. It is interesting to note that no interference must be anticipated with the newly-recognized myocardial infarction susceptibility gene on chromosome 14 [41]. However, a relation between PIA2-prevalence and cholesterol levels as well as with smoking upon ischaemic endpoints was reported clearly suggesting an interaction between the genotype and environmental factors [42,43].…”

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

“…Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect [7][8][9] . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 .…”

Cardiovascular Genetic Medicine: The Genetics of Coronary Heart Disease

“…In another linkage study, Broeckel et al studied a group of 513 unrelated families in which there was at least one member with a documented myocardial infarction. [9]. In this study, a region on chromosome 14 was linked to the myocardial infarction event; however, the putative causative gene(s) could not be identified further.…”