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Thesis Format

Integrated Article


Doctor of Philosophy




Hegele, Robert A.


Cardiovascular disease (CVD) is the primary cause of death globally and is estimated to cause one-third of deaths in Canada. Each year, millions of Canadians are affected by CVD despite ongoing efforts to reduce risk through lifestyle modifications and pharmacological therapies. With the expected rise in CVD prevalence due to the obesity epidemic, we need to better understand the genetic basis of heritable, modifiable risk factors, including levels of high-density lipoprotein (HDL) cholesterol and triglyceride, for insights into future therapeutic treatments and risk prediction. Through the use of a targeted next-generation sequencing panel designed specifically to study lipid and metabolic disorders, I have explored a spectrum of genetic variation—including rare and common variants, single-nucleotide and copy-number variants—in over 3,000 DNA samples isolated from individuals with abnormal lipid phenotypes, including: (i) hypoalphalipoproteinemia; (ii) hyperalphalipoproteinemia; and (iii) hypertriglyceridemia. From my research efforts, I demonstrated that the majority of individuals with abnormal HDL cholesterol levels did not carry many phenotypically-relevant genetic factors, but in those who did, rare variants were more prevalent in individuals with extremely low HDL cholesterol levels, while both rare variants and the accumulation of common variants were approximately equal in individuals with extremely high HDL cholesterol levels. Meanwhile, hypertriglyceridemia had a stronger genetic basis, with common variant accumulation being the most prevalent genetic determinant. Further, I uncovered that genetic determinants are more prevalent as the hypertriglyceridemia phenotype becomes more severe, and a genetic locus, CREB3L3, may have an extremely important, previously unappreciated role in hypertriglyceridemia susceptibility. By better understanding the genetic underpinnings of abnormal levels of HDL cholesterol and triglyceride, future efforts can explore the relationship between these phenotypes and their genetic determinants, and how we might leverage this information to develop better therapeutics to lower levels of these risk factors or create screening methods to identify individuals who might be at higher risk for CVD.

Summary for Lay Audience

Heart disease is the second leading cause of death in Canada and affects millions of individuals each year. Despite efforts to reduce disease risk with healthy lifestyles and medications, these strategies are not always successful. The variation in effectiveness may be linked to differences in an individual’s genetic make-up (i.e. DNA), and how these changes in DNA might be impacting levels of well-established risk factors for heart disease, such as: high-density lipoprotein (HDL) cholesterol—also referred to as the “good” cholesterol—and triglyceride (i.e. fats). These two lipid factors have been observed to associate with heart disease risk, and medications have been designed specifically to alter these lipid levels to reduce disease risk. Here, I worked to better understand the different DNA changes, also called “genetic variants”, that can influence levels of HDL cholesterol and triglyceride, and to specifically study the genetic variants in individuals with extreme lipid disorders characterized by either: (i) extremely low HDL cholesterol levels; (ii) extremely high HDL cholesterol levels; or (iii) extremely high triglyceride levels. After studying the DNA of over 3,000 individuals, I determined that each lipid disorder has a unique combination of rare and common genetic variants that help drive the presentation of each extreme lipid trait. During this research, I was also able to create two “genetic risk scores”—a method to aggregate information from many sites of common DNA variation into a single measure of disease risk—for both HDL cholesterol and triglyceride. From my collective research efforts, we now have a better understanding of the different DNA changes that can cause or increase risk for different lipid disorders, each of which have varying degrees of heart disease risk. By understanding the relevant genetic variants underlying lipid disorders involving abnormal levels of HDL cholesterol and triglyceride, future research efforts can explore how we might be able to take advantage of this information to develop better medications and therapeutics to lower levels of these heart disease risk factors or create genetic screening methods to identify individuals at higher risk for heart disease because of different types of genetic variation.

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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