Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism.
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.
Sijbrands
E J
EJ
Department of General Internal Medicine, Medical Faculty, Leiden University Medical Center, Leiden, The Netherlands. nrexpert@euronet.nl
Hoffer
M J
MJ
Meinders
A E
AE
Havekes
L M
LM
Frants
R R
RR
Smelt
A H
AH
De Knijff
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016632:Apolipoprotein A-I / Q000235:genetics; D053305:Apolipoprotein C-III; D053329:Apolipoprotein E2; D001054:Apolipoproteins A / Q000235:genetics; D001056:Apolipoproteins C / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005192:Family Health; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics*; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D014973:Xanthomatosis / Q000097:blood / Q000235:genetics
D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D053329:Apolipoprotein E2; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; C022205:apolipoprotein A-IV