HYPERTRIGLYCERIDEMIA AND THE APOLIPOPROTEIN-CIII GENE LOCUS - LACK OFASSOCIATION WITH THE VARIANT INSULIN-RESPONSE ELEMENT IN ITALIAN SCHOOL-CHILDREN

Hypertriglyceridemia is a common metabolic disorder with a major inher ited component. In some individuals the condition is suspected to occu r as a result of overproduction of apolipoprotein (apo)CIII, a major c onstituent of triglyceride-rich lipoproteins. Population studies have established an association with the apoCIII gene but the identity of t he causal mutation remains unknown. In the present study we have exami ned a series of six 5' polymorphic nucleotides (G(-935) to A, C-641 to A, G(-630) to A, deletion of T-625, C-482 to T, and T-455 to C) that lie within the promoter region of the apoCIII gene for evidence of pos sible involvement in disease susceptibility. The polymorphic nucleotid es at positions -455 and -482 reside within a negative insulin-respons e element. We show, in a community-based sample of 503 school children , that a DNA polymorphism (S2 allele) within the 3'-noncoding region o f the apoCIII gene was associated with elevated apoCIII and triglyceri de levels, but that the polymorphic nucleotides of the promoter were n ot. In addition, no obvious effect of any extended apoCIII promoter ha plotype on plasma apoCIII or triglyceride levels, over and above that conferred by the presence of the S2 polymorphic nucleotide, was detect ed. These results demonstrate that none of the 5' apoCIII polymorphism s can account for the association of the apoCIII gene locus with hyper triglyceridemia and, moreover, owing to linkage disequilibrium, raise the possibility that the region conferring susceptibility maps downstr eam, rather than upstream, of the apoCIII gene promoter sequences.