UBC Theses and Dissertations
Plasma lipoproteins : genetic influences and relevance to atherosclerotic and infectious diseases Trinder, Mark Edward
Plasma lipoproteins, such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein(a) are highly heritable traits and important biomarkers for atherosclerotic cardiovascular disease (ASCVD). LDL and lipoprotein(a) are atherogenic plasma lipoproteins that are often both elevated among individuals with familial hypercholesterolemia; a common, autosomal co-dominant disorder characterized by pathogenic DNA variants in the LDLR, APOB, and PCSK9 genes. These pathogenic variants impair the removal of LDL from the blood and lead to severe hypercholesterolemia and increased risk of ASCVD. Despite the ability to identify individuals with a genetic cause for familial hypercholesterolemia or elevated lipoprotein(a), one of the most challenging aspects in the clinical management of this patient population is the remarkable diversity of ASCVD risk. Alternatively, HDL has been thought to protect against atherosclerosis because low levels of HDL are strongly associated with increased risk of ASCVD. Several recent clinical trials have unsuccessfully attempted to raise HDL cholesterol to reduce the risk of ASCVD. These results have left unanswered questions about the primary function(s) of HDL. Plasma lipoproteins undergo extensive changes in structure, function, and metabolism during severe infections such as sepsis. However, the implications and causality of these changes to clinical outcomes is poorly understood. The central objective was to explore the contribution of genetic variation in plasma lipoprotein traits and metabolism on lipid disorders such as familial hypercholesterolemia, elevated lipoprotein(a), and serious infections such as sepsis. Here, we used genetic epidemiology and mouse models of disease to assess how common and rare germline genetic variation affects the risk of atherosclerotic cardiovascular diseases and infectious diseases. Specifically, 1) can background genetic variation related to LDL and lipoprotein(a) modify the risk of ASCVD for individuals with familial hypercholesterolemia? and 2) are associations between HDL and risk of infectious disease causal? Several broad conclusions can be made. First, background polygenic factors influencing LDL-C and lipoprotein(a) levels modify the penetrance and expressivity of familial hypercholesterolemia. Second, the primordial function of HDL may be related to immunoregulation and resolution of infection. Third, cholesteryl ester protein is an important regulator of HDL levels during sepsis and may be a therapeutic target.
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