Molecular genetics of coronary heart disease.

Abstract

Genes underlying the inheritance of atherosclerosis are implicated by family and twin studies. The aggregation of coronary artery disease in families has been reported by many Authors since 1948 (1). For example, Slack and Evans (,2) analysed first degree relatives of 121 men and 96 women with coronary artery disease. The increased risks of death from coronary artery disease in such relatives were five and seven-fold greater than in matched controls for males and females respectively. Familial clustering of coronary artery disease was noted especially for female patients. In Southern Finland, 104 out of 296 brothers of patients with coronary artery disease also had arterial disease compared to 8 out of 81 brothers of healthy controls (relative incidence 3.5 for brothers of probands with coronary artery disease (3) A detailed analysis of the Finish data yielded heritability estimates compatible with almost total determination of the disease by additive polygenic factors in the youngest age groups (myocardial infarction prior to the age of 46 years). In another study (4),of 207 patients who had myocardial infarcts before the age of 55 years, the highest “risk-ratios” calculated for nineteen independent variables were found with a positive family history of coronary artery disease (10.5) and lesser “risk ratios” were found with plasma cholesterol levels greater than 270 mg/dl. (4.3) cigarette smoking (4.0) and stroke in a first degree relative (3.5). The “risk ratio” for a family history of coronary artery disease was greater than that for individuals in the highest quintile of cholesterol levels. This observation may suggest that major genetic effects are not necessarily mediated by pathways of cholesterol metabolism. From this study, the heritability of coronary heart disease of early onset was calculated to be 0.63. If the families in which the proband had a monogenic hyperlipidaemia were eliminated, the heritability estimate remained as high as 0.56 (4). Equally, persuasive evidence comes from twin studies (5). Concordance rates for coronary artery disease (diagnosed by angina pectoris or myocardial infarction) in monozygotic twin pairs was found to be 0.65 compared to 0.25 in dizygotic twin pairs in a Norweigan Study.