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Thesis Format

Integrated Article


Master of Science




Hegele, Robert A.


Hypertriglyceridemia (HTG) is a risk factor for cardiovascular disease. However, only the triglyceride (TG) phenotype produced by biallelic loss-of-function (LOF) variants in the canonical TG metabolism genes is well understood. The TG phenotype produced by monoallelic LOF variants is poorly understood. We aimed to evaluate the TG phenotype associated with monoallelic LOF variants in the canonical TG metabolism genes.

Next-generation sequencing panel was employed to identify patients heterozygous for LOF variants in two of the canonical TG metabolism genes LPL and APOA5, followed by chart review to determine baseline and longitudinal TG phenotype in these patients.

My findings suggest that heterozygosity for LOF variants in these genes is associated with highly variable TG phenotype, both at baseline and longitudinally. Thus, my findings describe a unique, previously underappreciated TG phenotype and identification of these variants may serve as an early warning to physicians regarding difficulty in treating HTG in these patients.

Summary for Lay Audience

Cardiovascular diseases (CVD) are the leading cause of death and reduced quality of life globally. While effective public policy and improved emergency care and screening have reduced CVD deaths in many places, the rapidly aging and growing global population has caused these reductions to stagnate and even reverse in some areas. This has highlighted a need for better understanding of the underlying risk factors for CVD and their influences so that we can better combat CVD. One of the major risk factors for the development of CVD is elevated triglyceride (TG) levels in an individual’s blood – called hypertriglyceridemia (HTG) – which have been observed to be associated with increased CVD risk. Genetics (i.e., DNA) play a prominent role in the development of HTG. DNA changes (called genetic variants) can render an encoded protein non-functional. These are called loss-of-function (LOF) variants. Given that humans have two copies of every gene, complete loss of a protein’s functionality usually requires LOF variants in both copies. This is well understood to cause severe HTG resistant to treatment when it affects the proteins controlling TG levels. The impact of a LOF variant in only a single copy of these genes (called heterozygosity) on TG levels is not well understood. To better understand this, I studied the DNA and TG levels of 22 patients over varying time frames in a clinical setting who had a LOF variant in one of their TG level controlling genes and determined that LOF variants in these genes is associated with highly variable TG levels both at baseline and over time, with their TG levels often ranging between normal and extreme HTG levels, with no discernable pattern, which seems to be unique to patients with this genetic profile. Therefore, my research efforts have demonstrated clearly that heterozygosity for LOF variants in these genes produces a unique TG profile in these patients. Detection of heterozygosity for these variants may serve as an early warning for physicians regarding the potential difficulty in treating the HTG of these patients and indicate the need for careful monitoring of their TG levels.

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