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 denned by chemical criteria. None of the patients with DLPIII had tuberous or palmar xanthomas characteristic of classically denned type HI hyperlipoproteinemia. After exclusion of four persons with apo E 2-2 phenotype, there were 89 FH patients and 110 non-FH subjects. Definite DLPIII (denned 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 /3-VLDL cholesterol concentration. Estimated /3-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 /3-VLDL cholesterol between sexes. Correlation between estimated 0-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 /3-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. {Arteriosclerosis and Thrombosis 1991;11:1137-1146)

Hyperlipidemia of ApoE2(Arg 158 -Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression

“…34,35 These observations in the human agree with the present data on the relative importance of the LDL receptor for the clearance of lipoproteins containing even poorly binding apoE variants in the mouse. Thus, individual variation in the level of LDL receptor expression could play an important role in the expression of hyperlipidemia even in individuals expressing mutant forms of apoE that bind poorly to the LDL receptor.…”

Molecular Biology of Atherosclerosis

“…Interestingly, a subset of human FH patients who have both heterozygous LDLR mutations and an ApoE2 variant (and who clearly manifest type III hyperlipidemia in addition to high LDL) do not have higher risk than other persons with FH without type III hyperlipidemia (260,783,786). This may be due to reduced conversion of remnants to LDL and somewhat lower LDL levels in this combined lipid disorder.…”

Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred

“…FH patients often present with phenotypic heterogeneity, as plasma cholesterol levels can vary widely within the same pedigree; they may show increased plasma levels of triglyceride-rich lipoproteins in a variable spectrum that depends on segregation of other genetic loci. Potential influences of additional genetic factors on the variability and the severity of FH, such as modifier genes interacting with the LDLR mutation, have been assumed but rarely demonstrated Hopkins et al, 1991).…”