Apolipoprotein E phenotypes were determined in 361 patients with
hyperlipidemia and in controls. The E2
isoform was significantly more frequent in the group of hyperlipidemics (P less than 0.0005). This was not due to a higher frequency of E-2/2 homozygotes with
type III hyperlipoproteinemia, but rather to a significantly higher frequency of E2 heterozygotes (P less than 0.0005). Subgrouping of hyperlipidemics into patients with a)
hypertriglyceridemia, b)
hypercholesterolemia and c) mixed
hyperlipidemia revealed i) that
isoform E2 was significantly more frequent in patients with
hypertriglyceridemia (0.001 greater than P greater than 0.005), ii) that
isoform E4 was significantly more frequent in patients with
hypercholesterolemia (0.01 greater than P greater than 0.005) and iii) that
isoforms E2 (P less than 0.005) and E4 (0.05 greater than P greater than 0.025) were both more frequent in patients with mixed
hyperlipidemia. Roughly 20% of patients with mixed
hyperlipidemia had one of the rare phenotypes E-4/4, -4/2 or -2/2. We conclude that alleles epsilon 2 and epsilon 4 both contribute to the susceptibility for, and/or phenotypic expression of
hyperlipidemia. Whereas the gene epsilon 2 seems to exert its influence on plasma
lipoproteins by an abnormal gene product (E2) that has reduced binding activity to
lipoprotein receptors, the mechanism underlying the association of the epsilon 4 gene with
hyperlipidemia is presently unclear.