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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2722.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Severe Hyperlipidemia in Apolipoprotein E2 Homozygotes Due to a Combined Effect of Hyperinsulinemia and an SstI Polymorphism

Eric J. G. Sijbrands; Mariëtte J. V. Hoffer; A. Edo Meinders; Louis M. Havekes; Rune R. Frants; Augustinus H. M. Smelt; Peter De Knijff

From the Department of General Internal Medicine, Medical Faculty (E.J.G.S., A.E.M., A.H.M.S.), and the MGC–Department of Human Genetics (M.J.V.H., R.R.F., P.D.K.), Leiden University Medical Center, and TNO-PG, Gaubius Laboratory (L.M.H.), Leiden, Netherlands.

Correspondence to E.J.G. Sijbrands, Department of General Internal Medicine, Academic Medical Center, Amsterdam, c/o Overtoom 49, 1054 HB Amsterdam, The Netherlands. E-mail nrexpert{at}euronet.nl

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(Arg158Cys) 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.

Key Words: apolipoprotein E • hyperlipoproteinemia type III • hyperinsulinemia • xanthomas

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