Hypertriglyceridemia and
hyperlipidemia are common disorders associated with
coronary artery disease and premature death. The
proteins encoded by the
apolipoprotein (
apo) A-I/C-III/A-IV gene cluster are involved in the metabolism of both
triglycerides and
cholesterol. In a large sample of individuals from the ARIC study, six polymorphic markers were typed and plasma
lipid values were measured to determine whether the well-established association between the Sst I S2 allele in the 3'-untranslated region of the
apo C-III gene and
hypertriglyceridemia was due to disequilibrium with variation in the 5' regulatory region of the
apo C-III gene. The Sst I polymorphism was significantly associated with
hypertriglyceridemia (P = .006) but not with carotid artery wall thickness, plasma
apo C-III levels, or
elevated cholesterol. The frequency 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 polymorphisms were significantly associated with any of the plasma
lipids studied. There was substantial linkage disequilibrium between the Sst I polymorphism and each of the 5'
apo C-III polymorphisms; however, the significant association between the
apo C-III haplotypes and
hypertriglyceridemia (odds ratio, 4.0; P < .0001) was solely attributable to the effects of the Sst I polymorphism (odds ratio, 3.96). As a part of these analyses, we also defined a unique haplotype that is inversely associated with the occurrence of
hypertriglyceridemia, suggesting further molecular analyses of this important gene region.