Gene identification for complex cardiovascular lipid traits

Coronary artery disease (CAD) is the leading cause of mortality in western societies and an example of a common complex disease influenced by multiple, potentially interacting genes and environmental factors. Genetic studies of complex diseases have proven difficult and the genetic causes of CAD remain elusive. It is anticipated that early-onset cases and endophenotypes of CAD, such as serum lipid levels, will provide greater power for genetic studies of CAD. The focus of this dissertation was to identify genes and variants associated with serum lipid levels using candidate-gene and genome-wide approaches in both familial cases with early-onset disease and population-based samples.;We investigated a candidate gene hepatic nuclear factor 4 alpha (HNF4A) located in a region of suggestive linkage to high triglycerides in Finnish dyslipidemic families. HNF4A is a transcription factor involved in the regulation of serum lipid and glucose levels, and thus an excellent candidate gene for CAD. We showed for the first time that common HNF4A variants are associated with serum lipid levels. Importantly, we investigated this gene for association in dyslipidemic families originating from two ancestral groups, and both Finns and Mexicans shared the associated HNF4A variants. We also demonstrated that the association with HNF4A explains much of the original linkage signal.;We fine mapped a region on chromosome 16q that has been consistently replicated for HDL cholesterol in linkage studies using a two-stage association analysis of tag-SNPs in dyslipidemic families and case and control study samples. We identified a region-wide significant SNP in the WW domain-containing oxidoreductase (WWOX) gene that explains much of the linkage signal on 16q. Importantly, we also demonstrated a population effect for this variant in a cross-sectional cohort and a longitudinal effect in a population-based prospective cohort with measurements at four different time points over twenty one years. The identification of WWOX may suggest a new metabolic pathway as its function is currently unknown.;Mapping the defect of the combined lipase deficiency (cld) mice revealed that lipase maturation factor 1 (LMF1) is essential for the processing of both lipoprotein lipase and hepatic lipase. We investigated LMF1 in human dyslipidemias by resequencing the coding regions in individuals expressing the cld phenotype (i.e. hypertriglyceridemia with decreased lipase activity). We identified a homozygous mutation causing a premature termination codon that could not restore lipase activity in cld/cld cells. This was the first study to demonstrate that LMF1 is involved in human lipase deficiencies and dyslipidemia.;The Mexican population has an increased predisposition to dyslipidemias. However, no genome-wide association (GWA) or linkage studies have been performed in Mexicans to date. We utilized a two-stage replication based design of dyslipidemic families and case/control samples to screen for common variants influencing plasma lipids levels in Mexicans. An important consideration in this design is the markers taken forward to the second stage. Therefore to select SNPs for stage 2, we incorporated multiple lines of evidence by integrating complementary data from genome-wide linkage, association and co-expression networks in Mexicans and GWA results for lipids in Caucasians.;The results presented in this work illustrate the utility of different gene mapping strategies for complex cardiovascular traits, and demonstrate that complementary approaches, large samples and multiple ancestral groups will yield insight into novel genes and pathways for lipid metabolism and its associated risk of CAD.