Genetic polymorphism in human apolipoprotein E

This chapter provides the methodologies employed to study the polymorphism of human apoE. These and other related studies have advanced our understanding of the structure and function of this protein as follows: The complex array of human apoE observed by two-dimensional gel electrophoresis results from genetic variation and posttranslational modification. The genetic polymorphism of apoE is explained by the existence of three common alleles (epsilon 4, epsilon 3, epsilon 2) at a single structural gene locus. Combinations of above alleles can generate three homozygous (E4/4, E3/3, E2/2) and three heterozygous (E4/3, E3/2, E4/2) apoE phenotypes. The apoE phenotype E2/2 is found in 91% of patients with type III hyperlipoproteinemia and can be used as a molecular marker for the diagnosis of this disease. However, other rare or common apoE phenotypes have been observed in patients with type III HLP. ApoE originating from E2/2 phenotype (Arg 158 to Cys 158 substitution) has reduced affinity for the LDL receptor. This property of apoE2 can account partially for the accumulation of apoE-rich lipoprotein remnants in the plasma of patients with type III HLP. However, other genetic or environmental factors are necessary for the phenotypic expression of the disease.