Apolipoprotein E polymorphism and heterozygous familial hypercholesterolemia. Sex-specific effects.

Abstract

The impact of apolipoprotein (apo) E polymorphism on interindividual variation in plasma lipid, lipoprotein, and apolipoprotein levels was studied in a sample of familial hypercholesterolemic (FH) patients (147 women, 116 men) with the same mutation, a >10-kilobase deletion of the low-density lipoprotein (LDL) receptor gene. Each trait was adjusted for concomitants (age, age squared, height, weight, weight squared) for each sex separately before the apoE genotypic effects were estimated. The relative contribution of concomitants to sample variability was found to be very different in women and in men. Allelic variation in the apoE gene was shown to explain a statistically significant portion of the variability in adjusted lipid traits. Moreover, the contribution of apoE polymorphism was different between sexes. In women, there was significant variability (P<.01) among apoE genotypes for total cholesterol, LDL cholesterol, and total and LDL apoB. In men, significant variability (P<.01) was observed among apoE genotypes in very-low-density lipoprotein (VLDL) cholesterol and triglyceride levels. Women with the e3/2 genotype had significantly lower means for total choles-C oronary artery disease (CAD) is a complex disease explained by multiple interactions among the effects of many genetic and environmental factors. 1 -2 One of the intermediate traits between causes and the development of disease, plasma cholesterol, has long been recognized as a risk factor for CAD. Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized at the molecular level by one of a number of mutations in the low-density lipoprotein (LDL) receptor gene and high levels of plasma LDL cholesterol (LDL-C).3 " The average age of onset of symptomatic CAD in heterozygous FH is reported to be 43 years in men and 53 years in women. 5 In populations in which a founder effect has occurred, such as in French Canadians, shared mutations may be found in a large proportion of FH patients.6 Indeed, one of these mutations, a >10-kilobase deletion at the 5' end of the LDL receptor gene involving the promoter and exon 1, has been reported in 60% of French-Canadian FH patients. © 1994 American Heart Association, Inc.terol, LDL cholesterol, and LDL apoB than women with the e3l3 genotype (P<.05). In men, the mean VLDL cholesterol was significantly higher for the e2/2 genotype and was significantly lower for the e4l2 genotype than the mean for the (313 genotype (P<.05). Overall, the greatest influence was associated with the e2 allele, and the LDL cholesterol-lowering effect of this allele was present only in FH women. No statistically significant apoE effect was shown on lipoprotein(a) levels in either sex. Less than 20% of the variability for any of the lipid traits among FH patients with the >10-kb deletion is explained by the predictors considered in this study.Most of the remaining variability in lipid traits must be explained by other genetic or environmental factors. In conclusion, this study documents large effects of th...

Determinants of Lipid Level Variability in French-Canadian Children With Familial Hypercholesterolemia

“…This effect was not sex-specific. Ferrieres et al 7 showed a similar effect in French-Canadian FH women but not in men. Tonstad et al 16 did not detect any influence of apoE genotype on lipid levels of Norwegian FH children.…”

“…6 In healthy adults, between 4% and 8% of the total variance in plasma LDL-C concentrations can be attributed to the common apoE polymorphism. 6,7 ApoB is the major apolipoprotein of chylomicrons, VLDL, IDL, LDL, and lipoprotein(a) particles. The apoB gene located on chromosome 2 has numerous polymorphic sites, among which are those due to an insertion (Ins) or a deletion (Del) of 9 base pairs, which produces a difference of 3 amino acids in the signal peptide (for reviews, see Humphries and Talmud 8 and Vedie et al 9 ).…”

Phenotypic Variation in Heterozygous Familial Hypercholesterolemia

“…The possible influence of genetic factors other than variation at the LDLR gene locus could not be examined fully in this relatively small sample. Allelic variation in the genes for apoE, 28 apo(a), 29 angiotensin-converting enzyme, 30 and apoB 31 have been reported to affect lipoprotein concentrations and predisposition to premature CAD in subjects with FH, but these effects are relatively small. Data for the apo(a) and apoE phenotypes/genotypes were not available for the original Chinese FH patients, but it is unlikely that variation in these genes alone is a cause for the highly significant difference in phenotype observed in this study between the Chinese FH heterozygote cohorts of such similar racial origin.…”

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

“…28 APOE genotype alters lipoprotein particle distribution and number and triglyceride metabolism, and gender differences in these effects have been reported. 29,30 These observations suggest that the femalespecific protective effect of the APOE4 genotype on survival in CLL could relate to several mechanisms including modulation of CLL cell apoptosis by estrogen through the apoE/Akt pathway.…”