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Coronary heart dise...
Abstract
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- To this point in time, coronary heart disease (CHD) has been a major cause of morbidity and mortality in the industrialized part of the world. During the last decades a decrease in morbidity and mortality has been observed in the developed countries. The bases for this progress are mainly improvements in the health care system, medical interventions, and changes in people's lifestyle; habits related to an increased risk of the disease, like smoking, obesity and physical inactivity. In conclusion, this progress is mainly due to environmental changes. However, other factors, not possible to modify, like genetic factors, also contribute to the burden of CHD. Thus far, it has been shown that a positive family history of CHD increases risk. In addition, a large number of candidate genes have been suggested to be associated with CHD through related mechanisms such as lipid metabolism, blood pressure regulation, and insulin sensitivity. However, it has been difficult to quantify genetic influences by summarizing risks and effects of known genes, as the number of these genes is large and the effect of each gene small. The primary aim of this thesis was, therefore, to determine the overall impact of genetic and environmental factors on CHD-death and the CHD subphenotypes acute myocardial infarction (AMI) and angina pectoris (AP). The secondary aims were to study if genetic influences change with age and to what extent they are mediated through well known risk factors and AP. Twin pairs born between 1886 and 1958 from the Swedish Twin Registry were used to calculate concordances, hazard ratios and heritability. Heritability estimates were obtained by two approaches, the frailty and the liability approach. Analyses of concordances resulted in higher concordances for CHD in monozygotic (MZ) than dizygotic (M) twins as well as in higher estimates at younger ages. 1 Heritability for CHD-death was estimated to 0.57 (95 % Cl 0.45-0.69) among males and 0.38 (0.26-0.50) among females, and extension of the follow-up time resulted in a decrease in heritability with increasing length of follow-up (paper 1). Including known risk factors (smoking, obesity, hypertension, diabetes, level of education, and marital status) into genetic analyses resulted in a slight decrease of genetic variance and thus a slight portion (among males and more so among females) of genetic variance was accounted for by the genetic variance for studied risk factors (paper 11), AP was shown to be an important risk factor for CHD death in both sexes, although more so in males. Heritability analyses resulted in moderate heritability estimates for AP in both sexes (0.39 (0.29-0.49) in males and 0.43 (0.08-0.5 1) in females). The correlation between AP and CHD was almost entirely explained by the influence of familial factors in both sexes (paper 111). Heritability for AMI resulted also in moderate estimates, 0.35 (0.28-043) for males and 0.38 (0.290,46) for females (paper IV). In conclusion, genetic factors influence CHD-death to a moderate degree as well as the sub phenotypes AMI and AP. Genetic influences for death from CHD are slightly higher among males and more important at younger ages. Finally, genetic influences for CHD-death are slightly modified through risk factors and AP in males and more so in females.
Nyckelord
- Coronary heart disease, angina pectoris, acute myocardial infarction, twins, heritability, liability, frailty
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