Type III dyslipoproteinemia in patients heterozygous for familial hypercholesterolemia and apolipoprotein E2: Evidence for a gene-gene interaction

Abstract

In four large pedigrees with heterozygous familial hypercholesterolemia (FH) genetically linked to the low density lipoprotein receptor locus, we have observed a strong interaction between the presence of FH and a single apolipoprotein (apo) E2 allele, resulting in a markedly increased prevalence of type III dyslipoproteinemia (DLPIII). DLPIII was defined by chemical criteria. None of the patients with DLPIII had tuberous or palmar xanthomas characteristic of classically defined type III hyperlipoproteinemia. After exclusion of four persons with apo E 2-2 phenotype, there were 89 FH patients and 110 non-FH subjects. Definite DLPIII (defined as a very low density lipoprotein [VLDL] cholesterol to plasma triglyceride ratio >0.30 with plasma triglycerides ≥150 mg/dl) was present in 26% of 43 FH patients with a single E2 allele compared with only 3.4% of 29 non-FH subjects with an E2 allele (p=0.003). To further characterize this interaction we performed a two-way analysis of covariance, after adjustment for age, sex, and body mass index, to test for any interaction between FH and the apo E loci. There was a statistically significant interaction between FH and the presence of a single E2 allele for the ratio of VLDL cholesterol to plasma triglycerides and for a newly derived estimate of β-VLDL cholesterol concentration. Estimated β-VLDL cholesterol level was strongly correlated with age in the subgroup with FH and an E2 allele but not in other subgroups. There was no difference in estimated β-VLDL cholesterol between sexes. Correlation between estimated β-VLDL cholesterol level and body mass index in persons older than 18 years was of only marginal significance and of similar magnitude in persons with or without an apo E2 allele. Present knowledge suggests that β-VLDLs are highly atherogenic; if so, then a sizable subset of FH patients having at least one apo E2 allele and DLPIII may be at increased risk for premature coronary heart disease.