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 hype rtriglyceridemia, premature coronary artery disease (CAD), and familia l 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 mangan ese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protei n (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosom e 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in fam ilies 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 i n the FCH probands (39%) than in the spouse controls (4%). Evidence fo r linkage was observed at the MnSOD (P = .02), CETP/LCAT (P = .03), an d apolipoprotein AI-CIII-AIV loci (P = .005) but not at the LDLR locus . We conclude that there is a genetically based association between FC H and small, dense LDL and that the genetic determinants for LDL parti cle size are shared, at least in part, among FCH families and the more general population at risk for CAD.