The Genetic Determinants of Complex Lipid and Lipoprotein Phenotypes
Abstract
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.