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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 genes1. 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.

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Acknowledgements

We thank G. Klein for helping to establish the MI family database; members of these families for cooperation and consent; M. Pöll and S. Kürzinger for technical assistance; U. Hubauer for managing the phenotype evaluation; H. Xia for database assistance; J. Williams and L. Almasy for statistical advice; and J. Weber and the NHLBI Mammalian Genotyping Service for valuable contributions. U.B. and H.J.J. are supported in part by a grant from the National Heart, Lung, and Blood Institute. A.C. and J.B. are supported in part by a grant from the National Institutes of Health. We acknowledge the support from the Wilhelm-Vaillant-Stiftung, the Ernst-und-Berta-Grimmke-Stiftung, the Deutsche Herzstiftung and the Deutsche Forschungsgemeinschaft (to U.B., S.H., C.H. and H.S.).

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Correspondence to Howard J. Jacob or Heribert Schunkert.

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Figure 1: Linkage analysis results of the genome scan in 513 families.
Figure 2: Lod plot for MI on chromosome 14.
Figure 3: Multipoint lod score for serum lipoprotein (a) on chromosome 1.