Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biochemistry

Supervisor

Dr. Robert A. Hegele

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Canada. Among non-traditional risk factors, plasma triglyceride (TG) concentration is re-emerging as a significant risk factor. Patients with hypertriglyceridemia (HTG) – an archetypal complex phenotype defined by fasting plasma TG concentration >95th percentile – thus have significantly increased CVD risk, compounded by associated co-morbidities such as obesity, metabolic syndrome and type 2 diabetes. However, the molecular pathways contributing to HTG susceptibility are incompletely defined. A better understanding of the genetic determinants that underlie the phenotypic spectrum of plasma TG and HTG susceptibility is necessary to identify novel genes and pathways that could be targeted to effectively lower plasma TG and improve cardiovascular risk. Accordingly, we sought to characterize the genetic architecture of HTG susceptibility and phenotypic heterogeneity using several modern genomic technologies, including high-density microarray genotyping and high-throughput resequencing of candidate genes in HTG patients and healthy controls. We demonstrate that a broad allelic spectrum of common small effect variants and rare large effect variants is associated with HTG. Furthermore, we demonstrate that significant overlap exists between genes and variants that modulate plasma TG and increase HTG susceptibility. Taken together, we suggest that HTG susceptibility is the result of a genetic burden of TG-raising alleles in genes that modulate plasma TG concentration. These findings provide a breadth of novel targets for pharmaceutical development in hopes of reducing plasma TG concentration and improve cardiovascular risk in HTG patients.

Download

Share

COinS