ASSOCIATIONS OF ALLELIC DIFFERENCES AT THE A-I C-III/A-IV GENE-CLUSTER WITH CAROTID-ARTERY INTIMA-MEDIA THICKNESS AND PLASMA-LIPID TRANSPORT IN HYPERCHOLESTEROLEMIC-HYPERTRIGLYCERIDEMIC HUMANS/

Individuals with elevated levels of plasma cholesterol and triglycerid e may be at higher risk for coronary artery disease than those with is olated elevations of either cholesterol or triglyceride. Sequence vari ation in the A-I/C-III/A-IV gene cluster has been implicated in the et iology of some disorders associated with premature atherosclerosis and /or hypertriglyceridemias with or without elevations of cholesterol. T his led to the hypothesis that allelic variation at this gene locus al ters plasma lipid transport and affects susceptibility for atheroscler osis. The study population, from the Atherosclerosis Risk in Communiti es (ARIC) Study, consisted of 50 normolipidemic individuals, 48 subjec ts with elevated plasma cholesterol, 47 subjects with elevated plasma triglyceride, and 123 subjects with both elevated plasma cholesterol a nd triglyceride who were used to evaluate associations between an Xmn I polymorphic site 2.5 kilobase pairs (kbp) upstream of the structural gene for apolipoprotein (ape) A-I, intimal-medial thickening of the e xtracranial carotid arteries, and several plasma lipid factors. The re lative allele frequencies of the 8.3-kbp allele and the 6.6-kbp allele were .86 and .14, respectively, in the entire study population and di d not differ among the lipid phenotypes. In the group with elevated pl asma cholesterol and triglyceride, subjects possessing the 6.6-kbp all ele exhibited a greater carotid artery intimal-medial thickness (P=.03 4) and higher plasma levels of apoA-I, high-density lipoprotein (HDL) cholesterol, and HDL, cholesterol (P<.02) than subjects homozygous for the 8.3-kbp allele. In contrast, subjects with the 6.6-kbp allele dis played lower mean ratios of apolipoproteins C-II to C-III, C-II to A-I V, and E to A-IV in plasma (P<.05) and a lower mean ratio of apolipopr otein C-II to C-III in the triglyceride-rich lipoproteins (P=.026). Se quence variation in or near the genes encoding apolipoproteins A-I, C- III, and A-IV may therefore identify a group of hypercholesterolemic-h ypertriglyceridemic persons who are at higher risk for atherosclerosis than others with the same lipoprotein phenotype.