POLYMORPHIC MARKERS IN APOLIPOPROTEIN C-III GENE FLANKING REGIONS ANDHYPERTRIGLYCERIDEMIA

Hypertriglyceridemia and hyperlipidemia are common disorders associate d with coronary artery disease and premature death. The proteins encod ed by the apolipoprotein (apo) A-I/C-III/A-IV gene cluster are involve d in the metabolism of both triglycerides and cholesterol. In a large sample of individuals from the ARIC study, six polymorphic markers wer e typed and plasma lipid values were measured to determine whether the well-established association between the Sst I S2 allele in the 3'-un translated region of the apo C-III gene and hypertriglyceridemia was d ue to disequilibrium with variation in the 5' regulatory region of the apo C-III gene. The Sst I polymorphism was significantly associated w ith hypertriglyceridemia (P=.006) but not with carotid artery wall thi ckness, plasma apo C-III levels, or elevated cholesterol. The frequenc y of the S2 allele was 0.14 in those with high triglyceride levels and 0.05 in those with low triglyceride levels. None of the 5' flanking p olymorphisms were significantly associated with any of the plasma lipi ds studied. There was substantial linkage disequilibrium between the S st I polymorphism and each of the 5' apo C-III polymorphisms; however, the significant association between the apo C-III haplotypes and hype rtriglyceridemia (odds ratio, 4.0; P<.0001) was solely attributable to the effects of the Sst I polymorphism (odds ratio, 3.96). As a part o f these analyses, we also defined a unique haplotype that is inversely associated with the occurrence of hypertriglyceridemia, suggesting fu rther molecular analyses of this important gene region.