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Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia Hill, John Stuart


Familial hypercholesterolemia (FH) is an autosomal dominant disorder in which the primary defect is a mutation in the LDL receptor. Heterozygous FH is among the most common inborn errors of metabolism and remains as the best example of an inherited defect causing premature coronary artery disease (CAD). This thesis describes the physical and biochemical characteristics of heterozygous FH in a large cohort consisting of 208 women and 156 men. The influence of both genetic and environmental factors on the clinical expression of FH were investigated to better understand the phenotypic variation within FH and thus improve the prediction and treatment of CAD in affected individuals. The general incidence of CAD in this population was lower compared to previous reports but the differences between the sexes were expected. It was shown that men had a much higher frequency of CAD (31%) compared to women (13%) despite having lower concentrations of total and LDL cholesterol. In addition, the average age of onset of coronary symptoms was delayed in females, 55 years compared to 48 years for males. A greater risk of developing CAD for men was associated with low levels of HDL cholesterol and a history of smoking. In women, however, CAD was associated with elevated triglyceride levels and the presence of hypertension. In order to efficiently assess the influence of the co-inheritance of the apolipoprotein E polymorphism in this large FH population, a novel apo E phenotyping procedure was developed. Phenotypes were determined directly from plasma which was neuraminidase treated, delipidated and focused in polyacrylamide minigels. The accuracy of this method was confirmed by making a comparison to the established procedure of phenotyping by isoelectric focusing of delipidated VLDL. The low cost, speed and simplicity of the minigel methodology provided ideal conditions to phenotype a large patient population. The frequencies of the ɛ2, ɛ3 and ɛ4 alleles of apolipoprotein E in 125 unrelated FH subjects did not differ significantly from the normal population. In addition, there was no apparent relationship between apo E4 and the concentration of any of the parameters in the plasma lipid profile. However, the presence of the E2 isoform was associated with significantly elevated triglycerides in both sexes. From this study, it is evident that the mutant FH gene exerts its effect within a system of interacting environmental and polygenic factors that are known to modify atherosclerotic risk. It has been established that the dissimilarity in the frequency of CAD between men and women is related to differences between the impact of known risk factors and the incidence of CAD. Therefore, the importance of the influence of these risk factors and the differences between men and women should be emphasized when treating and predicting the development of CAD in patients with FH.

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