UBC Theses and Dissertations
Identification and the relationship between mutations in the lipoprotein lipase gene, dyslipidemia and coronary heart disease Gagné, S. Eric
Lipoprotein lipase (LPL) is a critical enzyme which primary function is to hydrolyze triglycerides from triglyceride-rich particles in the circulation. LPL deficiency is a rare disease with a frequency of approximately 1 per million individuals. Affected individuals present with chylomicronemia and often develop pancreatitis, xanthomatas and hepatosplenomegaly. Heterozygote carriers of a LPL null allele are present in the population at approximately 1 per 500 individuals worldwide and manifest with reduced HDL-C, reduced apoA-I and increased VLDL and VLDL-triglycerides. The central role that LPL plays in plasma lipid homeostasis suggests that LPL may represent an important susceptibility gene for coronary heart disease through modulation of HDL-C and triglyceride levels. This hypothesis has remained largely untested given the difficulty of collecting large number of affected individuals. We postulated that the LPL gene might underlie common mutations in the population which may modulate plasma lipids and the risk for coronary heart disease. For this, we screened a group of 31 French Canadian patients with familial combined hyperlipidemia (FCHL) and a group of 120 coronary artery disease (CAD) male patients with low LPL activity for mutations in the LPL gene. Our results indicate that while no mutation in the LPL gene could account for a significant proportion of FCHL patients, three (3) mutations (D9N, N291S and S447*) were found at relatively high frequency (4.6%, 5.4% and 18.5% respectively) in the entire cohort of CAD patients (820 patients; REGRESS Study). In vitro characterization of these three mutations using in vitro mutagenesis and transient expression in COS-1 cells indicates that all three mutations lead to impaired secretion and/or impaired function of the protein, providing evidence of the functionality of these variants. In the REGRESS cohort, the D9N and N291S mutations were associated with decreased HDL-C. In contrast, the S447* mutation was associated with an increased HDL-C level and decreased triglyceride level. In addition, in a two-year follow-up of the REGRESS Study, carriers of the D9N allele showed increased progression of atherosclerosis compared to non-carriers. To further assess the impact of these variants at the population level, 2258 DNA specimens (1114 men and 1144 women) of the Framingham Offspring Study were analyzed for the three LPL mutations (D9N, N291S and S447*). Our result show that these LPL variants are associated with differences in HDL-C and triglyceride levels in men in the general population with the D9N and N291S mutation being associated with lower HDL-C and higher triglycerides. In contrast, the S447* allele is associated with higher HDL-C, lower triglycerides and confers significant protection against coronary heart disease in men. Together, our results present strong evidence that common variants in the LPL gene are significant modulators of plasma lipid concentration and risk for coronary heart disease in men in the general population.
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