Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.
Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD.
Department of Microbiology and Molecular Genetics, Department of Medicine, and Molecular Biology Institute, University of California, USA.
H
H
Allayee
B E
BE
Aouizerat
R M
RM
Cantor
G M
GM
Dallinga-Thie
R M
RM
Krauss
C D
CD
Lanning
J I
JI
Rotter
A J
AJ
Lusis
T W
TW
de Bruin
D000328:Adult; D016632:Apolipoprotein A-I / Q000235:genetics; D053304:Apolipoprotein C-II; D001054:Apolipoproteins A / Q000235:genetics; D001056:Apolipoproteins C / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002885:Chromosomes, Human, Pair 16; D002888:Chromosomes, Human, Pair 19; D002896:Chromosomes, Human, Pair 6; D003327:Coronary Disease / Q000235:genetics*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D006023:Glycoproteins; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D044465:White People / Q000235:genetics
D016632:Apolipoprotein A-I; D053304:Apolipoprotein C-II; D001054:Apolipoproteins A; D001056:Apolipoproteins C; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C022205:apolipoprotein A-IV; D013482:Superoxide Dismutase; D007862:Phosphatidylcholine-Sterol O-Acyltransferase