UBC Theses and Dissertations
Lipoprotein lipase and the ATP binding cassette transporter ABCA1 : two genes regulating plasma high density lipoprotein cholesterol and triglyceride levels and risk of coronary artery disease Clee, Susanne M.
Elevated plasma triglyceride (TG) levels are independent risk factors for atherosclerotic coronary artery disease (CAD). In contrast, increased high density lipoprotein cholesterol (HDL-C), is associated with protection against CAD. These studies investigated the relationship between alterations in two genes involved in TG and HDL metabolism, lipoprotein lipase (LPL) and the ATP-binding cassette transporter ABC A1, plasma lipid levels and atherosclerosis. Following initial studies validating the use of the mouse as an animal model in which to study the effects of LPL on atherosclerosis, data from apolipoprotein E deficient and cholesterolfed C57BL/6 mice demonstrated that the role of LPL in atherosclerosis is dependent on the site from which it is expressed. Increased plasma LPL activity is anti-atherogenic, while increased LPL protein within the blood vessel wall is pro-atherogenic. Similar trends were demonstrated in a feline model of LPL deficiency. Three common LPL polymorphisms (cSNPs) are associated with altered lipid levels and severity of CAD. These studies have shown that: the N291S variant is associated with decreased enzymatic activity, and an increased postprandial TG response; the D9N variant is associated with decreased LPL secretion, increased TG, and is in linkage disequilibrium with the g(-93)t variant (itself associated with decreased TG); and the S447X variant is associated with both decreased TG and blood pressure, which may account for its reduction in atherosclerosis independent of its effects on lipids. Our identification of ABCA1 demonstrated it is an important determinant of plasma HDLC levels. Heterozygosity for ABCA1 mutations is associated with decreased plasma HDL-C, increased TG, and a three-fold increased risk of CAD compared to unaffected relatives. The residual efflux activity in carriers of each mutation is a strong predictor of plasma HDL-C levels and CAD. Several cSNPs in the ABCA1 gene were identified, and were associated with plasma lipid levels and the severity of CAD. The R219K cSNP is associated with increased plasma HDL-C, decreased TG and decreased atherosclerosis, while others showed moderate effects on plasma lipid levels and/or the severity of atherosclerosis. In conclusion, genetic variation in both LPL and ABCA1 influences plasma TG and HDLC levels, and significantly alters the severity of atherosclerosis.
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