Identification and analysis of candidate genes for coronary artery calcification.

Abstract

Coronary artery calcification (CAC), quantified by electron beam computed tomography, is an effective, non-invasive means for detection of extent of coronary atherosclerosis in asymptomatic; and symptomatic individuals. There are several aspects of CAC quantity that make genetic studies of it particularly challenging. These include the non-normality of CAC frequency distributions, the complex nature of the trait and the strong age- and sex-dependence of CAC levels. It is well recognized that coronary artery disease (CAD) and CAC are complex processes that are influenced by genetic, as well as environmental, factors. There has been a great deal of variation in results from studies attempting to identify specific genes for these traits. Methods targeted to detection of small, context-specific effects and which take into account the complex statistical distribution of this quantitative trait need to be implemented in order to allow detection of genetic effects influencing CAC quantity. In order to investigate genetic factors influencing CAC quantity, two candidate gene studies and a genome-wide scan were conducted based on samples from the Epidemiology of Coronary Artery Calcification Study and the Genetic Epidemiology Network of Arteriopathy (GENOA). The first paper, which presents results from a study examining two polymorphisms in the gene for the beta-2 adrenergic receptor, resulted in evidence that this gene may modify the relationship between certain established CAD risk factors (e.g. triglycerides) and CAC. The second paper provides support for a possible epistatic effect between the genes for angiotensinogen and angiotensin-converting enzyme in their influence on CAC. The genome-wide scan based on anonymous markers in a sample of 29 families enriched for hypertension detected regions on chromosomes 6 and 10 that may harbor genes involved in high sex- and age-specific levels of CAC. The results from this dissertation support a genetic component to CAC and demonstrate the need for non-traditional analysis approaches. Confirmatory analyses for all three studies are needed to substantiate and further clarify the associations reported here.