Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism
article
More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158→Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)<0.001) and VLDL triglyceride (P(insulin by SstI)<0.01) and low levels of HDL (P(insulin by SstI)<0.02). In the normoinsulinemic group, no such relation of the SstI polymorphism with hyperlipidemia was observed. These data provide the first evidence for a combined effect of hyperinsulinemia and the SstI polymorphism on the expression of hyperlipidemia in apoE2 homozygotes.
Topics
Apolipoprotein EHyperinsulinemiaHyperlipoproteinemia type IIIXanthomasAdultAgedAged, 80 and overApolipoprotein A-IApolipoprotein C-IIIApolipoprotein E2Apolipoproteins AApolipoproteins CApolipoproteins ECholesterol, HDLCholesterol, LDLCholesterol, VLDLFamily HealthFemaleGene ExpressionHaplotypesHomozygoteHumansHyperinsulinismHyperlipidemiasMaleMiddle AgedPedigreePolymorphism, Single NucleotidePromoter Regions (Genetics)Xanthomatosis
TNO Identifier
235224
ISSN
10795642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 19(11), pp. 2722-2729.
Pages
2722-2729
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