Apolipoprotein E2 exists in 2 main isoforms, arg158 and cys158 (Rall et al., 1982; Gill et al., 1985). The second isoform (arg158-to-cys; R158C) was found in 98 of 100 E2 alleles by Emi et al. (1988). The other isoforms that give a band at the E2 position with isoelectric focusing include E2(lys146-to-gln) (107741.0011) and E2(arg145-to-cys; 107741.0004). Type III hyperlipoproteinemia is typically associated with homozygosity for a change in apolipoprotein E2 from arg158 to cys.
By generating mice with a human APOE*2 allele in place of the mouse Apoe gene via targeted gene replacement in embryonic stem cells, Sullivan et al. (1998) demonstrated that a single amino acid difference (R158C) in the APOE protein is sufficient to cause type III hyperlipoproteinemia and spontaneous atherosclerosis in mice. Mice expressing human APOE2 (2/2) had virtually all the characteristics of type III hyperlipoproteinemia. Both their plasma cholesterol and triglyceride levels were 2 to 3 times those in normolipidemic mice that expressed human APOE3 (3/3) generated in an identical manner. The 2/2 mice were markedly defective in clearing beta-migrating VLDL particles and spontaneously developed atherosclerotic plaques, even on a regular diet. An atherogenic diet, high in fat and cholesterol, exacerbated development of atherosclerosis and xanthomas in the 2/2 mice.
In 72 patients with type III hyperlipidemia (617347) and the APOE 2/2 genotype, Evans et al. (2005) found a significantly higher frequency for at least 1 minor allele of the APOA5 -1131T-C and S19W (606368.0002) SNPs in patients than in controls (53% vs 19.7%, respectively; p = 0.0001). Evans et al. (2005) concluded that genetic variation in the APOA5 gene is an important cofactor in the development of type III hyperlipidemia.
