COMPLEX GENETIC CONTRIBUTION OF THE APO AI-CIII-AIV GENE-CLUSTER TO FAMILIAL COMBINED HYPERLIPIDEMIA - IDENTIFICATION OF DIFFERENT SUSCEPTIBILITY HAPLOTYPES

Familial combined hyperlipidemia (FCH) is a common genetic lipid disor der in Western societies. In a recent report (Dallinga-Thie, G.M., X.D . Bu, M. van Linde-Sibenius Trip, J.I. Rotter, A.J. Lusis, and T.W.A. de Bruin. J. Lipid Res., 1996, 36:136-147) we have studied three restr iction enzyme polymorphisms: XmnI, and MspI sites 5' of the apo AI gen e and SstI site in the 3' untranslated region of exon 4 of the apo CII I gene in 18 FCH pedigrees, including 18 probands, 178 hyperlipidemic relatives, 210 normolipidemic relatives, and 176 spouses. DNA variatio ns in the apo AI-CIII-AIV gene cluster had a modifying effect on plasm a triglycerides, LDL cholesterol, and apolipoprotein CIII levels. In t his study, combinations of haplotypes were analyzed to further charact erize their interactions and effect on the expression of severe hyperl ipidemia in FCH subjects. A specific combination of haplotypes with on e chromosome carrying the X1M1S2 (1-1-2) haplotype and the other the X 2M2S1 haplotype (2-2-1) was significantly more frequent in hyperlipide mic relatives (6%) than in normolipidemic relatives (3%) and spouses ( 0.5%). Associated with this combination of haplotypes were significant ly elevated plasma cholesterol (P < 0.0001), triglycerides (P < 0.0001 ), and apo CIII (P < 0.001) levels when compared to the wild type comb ination of haplotypes 1-1-1/1-1-1. The only spouse with this specific combination of haplotypes showed a severe hyperlipidemic phenotype, si milar to FCH. Furthermore, nonparametric sibpair linkage analysis reve aled significant linkage between these markers in the gene cluster and the FCH phenotype (MspI P = 0.0088, SstI P = 0.044, and XMS haplotype P = 0.037). The present findings confirm that the apo AI-CIII-IV gene cluster contributes to the FCH phenotype, but this contribution is ge netically complex. An epistatic interaction between different haplotyp es of the gene cluster was demonstrated. The S2 allele on one haplotyp e was synergistic to the X2M2 allele on the other haplotype in its hyp erlipidemic effect. Therefore, two different susceptibility loci exist in the gene cluster, demonstrating the paradigm of complex genetic co ntribution to FCH.