Title
Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism
Author
Sijbrands, E.J.G.
Hoffer, M.J.V.
Meinders, A.E.
Havekes, L.M.
Frants, R.R.
Smelt, A.H.M.
de Knijff, P.
Gaubius instituut TNO
Publication year
1999
Abstract
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.
Subject
Apolipoprotein E
Hyperinsulinemia
Hyperlipoproteinemia type III
Xanthomas
Adult
Aged
Aged, 80 and over
Apolipoprotein A-I
Apolipoprotein C-III
Apolipoprotein E2
Apolipoproteins A
Apolipoproteins C
Apolipoproteins E
Cholesterol, HDL
Cholesterol, LDL
Cholesterol, VLDL
Family Health
Female
Gene Expression
Haplotypes
Homozygote
Humans
Hyperinsulinism
Hyperlipidemias
Male
Middle Aged
Pedigree
Polymorphism, Single Nucleotide
Promoter Regions (Genetics)
Xanthomatosis
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TNO identifier
235224
ISSN
1079-5642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 19 (11), 2722-2729
Document type
article