Beyond genome wide discovery: an exploration of novel genetic variants for coronary heart disease

Recent developments spurred on by the Human Genome Project have for the first time permitted genome wide association studies leading to identification of multiple novel variants for complex diseases. This thesis consists of a series of studies exploring recent genetic findings for coronary heart disease (CHD) within the broader context of the promises of the genomic era that new findings would ultimately lead to 1) Identification of new disease mechanisms 2) Permit genotype based risk prediction and 3) Promote development of novel and targeted therapies based on genotype. We sought to address these questions, using the Emory Genebank, a collection of angiographically phenotyped subjects with stored blood samples and long-term follow up. We first refined the phenotype for CHD to help understand underlying mechanism and demonstrated differential associations between 8 novel risk variants including 9p21, and sub-phenotypes of CHD and thereby proposed differing mechanisms of risk for these loci. With two non-CHD cohorts we then demonstrated further association between one particular risk variant at 6p24 and the intermediate phenotype of arterial elasticity and related this to a potential novel mechanism of risk. Despite significant association with first events in population cohorts, we showed that these risk variants including 9p21 have limited value in secondary risk prediction, failing to demonstrate any association with prospective events in our cohort as single markers or when combined into a cumulative genetic risk score. Finally in subjects carrying leukotriene pathway CHD risk variants, we administered an oral leukotriene synthesis inhibitor and after just 4 week of therapy observed significant improvement in their endothelial function. In summary, these studies demonstrate the value of refining the phenotype to understand potential mechanisms, the complexities of genetic risk prediction and the feasibility and benefit of targeting therapy based on risk genotype