Two Loci on Chromosomes 2 and X for Premature Coronary Heart Disease Identified in Early- and Late-Settlement Populations of Finland

Abstract

Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. To assess the genetic background of CHD, we performed a genomewide linkage scan in two study samples from the genetically isolated population of Finland. An initial study sample consisted of family material from the northeastern part of Finland, settled by a small number of founders approximately 300 years ago. A second study sample originated from the southwestern region of Finland, settled approximately 2,000 years ago. Families were ascertained through probands exhibiting premature CHD, defined as >50% stenosis of at least two coronary arteries at a young age, as verified by coronary angiography. Both study samples and the pooled data set provided evidence for linkage in two chromosomal regions. A region on chromosome 2q21.1-22 yielded two-point LOD scores of 3.2, 1.9, and 3.7, in the affected sib-pair (ASP) analyses of the northeastern, southwestern, and pooled study samples. The corresponding multipoint maximum-likelihood scores (MLSs) for these three study samples were 2.4, 1.3, and 3.0. In addition, a region on chromosome Xq23-26 resulted in two-point LOD scores of 1.9, 3.5, and 2.9 and in multipoint MLSs of 3.4, 3.1, and 2.5, respectively. In conclusion, this study identifies two loci likely to contribute to premature CHD: one on chromosome 2q21.1-22 and another on chromosome Xq23-26.

Premature coronary artery disease shows no evidence of linkage to loci encoding for tissue inhibitors of matrix metalloproteinases

“…However, both of these scenarios would have less impact on public health issues or the development of new treatment strategies, although particularly a rare polymorphism with a strong effect could be of great importance to the individual. Our findings are also supported by the results of the genome-wide screens that have been published in the field of premature coronary artery disease (Pajukanta et al 2000, Francke et al 2001, Broeckel et al 2000, Harrap et al 2002. In none of these studies have potentially important LOD scores (>1) been reported for these regions.…”

“…However, it is important to note that the number of affected sibling pairs recruited into our study was larger than that of all four recently published genome-wide screens (Pajukanta et al 2000, Francke et al 2001, Broeckel et al 2000, Harrap et al 2002. Compared to genome-wide screens, our study will also have superior power to exclude linkage to the relevant loci because the recombination fraction approaches zero in our design (Risch 1990a, John et al 1997.…”

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 .…”

The genetics of cardiovascular disease: new insights from emerging approaches

“…Although CAD can also rarely be inherited in a Mendelian fashion (predominantly in conditions leading to elevated LDL), this only accounts for a small proportion of incident cases [7], most of which are likely to be polygenic. Linkage studies of non-Mendelian CAD have provided some unbiased associations [8][9][10][11][12][13][14][15][16], even though these have conspicuously lacked reproducibility between cohorts. However, linkage studies will always suffer from poor statistical power and the lack of detailed genomic mapping provided by conventional microsatellite markers.…”