Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia.
Apolipoprotein A-II (apoA-II) is a major protein on high-density lipoprotein (HDL) particles, and in mice, its levels are associated with triglyceride and glucose metabolism. In particular, transgenic mice overexpressing apoA-II exhibit hypertriglyceridemia, increased body fat, and insulin resistance, whereas apoA-II-null mice have decreased triglycerides and increased insulin sensitivity. Given the phenotypic overlap between familial combined hyperlipidemia (FCH) and apoA-II transgenic mice, we investigated the relationship of apoA-II to this disorder. Despite having lower HDL-cholesterol (HDL-C), FCH subjects had higher apoA-II levels compared with unaffected relatives (P<0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II, demonstrating that apoA-II variation is associated with several FCH-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h2=0.15; P<0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (LOD=3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (LOD score=1.4). Thus, this locus may have pleiotropic effects on apoA-II and FCH traits. Our results demonstrate that apoA-II is biochemically and genetically associated with FCH and may serve as a useful marker for understanding the mechanism by which FCH develops.
Allayee
Hooman
H
Department of Human Genetics, Gonda Genetics Research Center, of California, Los Angeles, Calif 90095, USA. hallayee@ucla.edu
Castellani
Lawrence W
LW
Cantor
Rita M
RM
de Bruin
Tjerk W A
TW
Lusis
Aldons J
AJ
D000328:Adult; D016633:Apolipoprotein A-II / Q000097:blood*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008875:Middle Aged
D016633:Apolipoprotein A-II; D008055:Lipids