APOLIPOPROTEIN A-I C-III/A-IV GENE-CLUSTER IN FAMILIAL COMBINED HYPERLIPIDEMIA - EFFECTS ON LDL-CHOLESTEROL AND APOLIPOPROTEIN-B AND APOLIPOPROTEIN-C-III/

The underlying generic abnormalities in familial combined hyperlipidem ia (FCH) hale not been elucidated, although previous association and l inkage studies hale implicated the apoA-I/C-III/A-IV gene cluster. We now report studies of this cluster in 18 probands, 390 family members (hyperlipidemic relatives, n = 179; normolipidemic relatives, n = 211) , and 177 spouses. Three restriction enzyme polymorphisms, XmnI and Ms pI sites 5' of the apoA-I gene and the SstI site in the 3' untranslate d region of exon 4 of the apoC-III gene, were examined. In hyperlipide mic relatives and FCH probands, the frequency of each minor allele was significantly higher than in spouses. Associated with the higher freq uency of minor alleles were elevated plasma cholesterol, triglycerides , LDL-cholesterol, apoB. and apoC-III levels. Quantitative sib-pair an alysis revealed linkage between the MspI minor allele and plasma LDL c holesterol levels (P < 0.04). The present data indicate that, while ap oA-I/C-III/A-IV gene cluster is nor the primary cause of FCH, this clu ster has a specific modifying effect on plasma triglyceride and LDL ch olesterol levels.