Premature Coronary Artery Disease - Clinical and Molecular Genetic Aspects

Since finishing the sequencing of the human genome in 2003, genetic research in coronary artery disease (CAD) and other complex traits have developed dramatically. Recent genome-wide association studies have identified a considerable number of common genetic variants each associated with the disease. This has led to a new understanding but also to the discovery of new therapeutical targets. However, each of the variants discovered only have minor effects on disease development and even the pooling of the variants only explains a minor percentage of the total heritability. It has been evident that rare or private mutations probably play a great role in the genetic architecture of CAD, especially among young and severely affected patients. These may only be identified by sequencing. Therefore, the investigators hypothesize, that the use of exome sequencing (the read-off of the entire protein-coding regions of the genome) and linkage analysis in families of extreme phenotype cases, will identify disease-causing genetic variants. From the West Denmark Heart Registry the investigators will enroll a minimum of 120 patients with atherosclerosis who have undergone a coronary artery revascularization procedure before the age of 40, to participate in study part 1. A pedigree analysis will be performed and cardiovascular (CVD) risk factors and current preventive treatment will be evaluated. 1. degree relatives aged 30-65 years, who are free of CAD, are invited to participate in study 2. CVD risk factors are evaluated as well as a CT coronary angiogram is performed to quantify the degree of asymptomatic coronary atherosclerosis. Families from study 1 and 2, who are considered severely affected by atherosclerosis, evaluated on a basis of family size, number of affected and severity of disease, will be selected for exome sequencing. Other relevant family members will be included as well as their CVD risk factors will be evaluated. Exome sequencing will be performed and variants found will be filtered on a basis of frequency, linkage analysis, gene position, existing knowledge and in-silico prediction tools. Possible findings will be validated by Sanger-sequencing and causality of new variants will subsequently be sought to be proven by relevant experimental studies.