AN APOLIPOPROTEIN CIII HAPLOTYPE PROTECTIVE AGAINST HYPERTRIGLYCERIDEMIA IS SPECIFIED BY PROMOTER AND 3' UNTRANSLATED REGION POLYMORPHISMS

Five DNA polymorphisms were detected in the promoter of the apolipopro tein CIII gene of a type III hyperlipidemic subject with severe hypert riglyceridemia (HTG). The polymorphic sites were C-641 --> A, G-630 -- > A, T-625 --> deletion, C-482 --> T, and T-455 --> C, With the previo usly reported base at each site designated allele 1 and the variant ba se designated allele 2. The sites were in strong linkage disequilibriu m with each other and with a polymorphic Sst I site in the apolipoprot ein CIII 3' untranslated region whose presence (S2 allele) has previou sly been shown to be associated with HTG. The distribution of haplotyp es of the form -625 -482 Sst I among 78 normolipidemic adults and 79 a dults with severe HTG was estimated by maximum likelihood analysis. Th e 211 haplotype was estimated to be 3.8-fold more common in normal sub jects than in HTG subjects (estimated proportions, 0.186 and 0.049, re spectively). This haplotype was associated with reduced HTG risk (rela tive risk, 0.28; P = 0.005) when compared with other haplotypes lackin g the Sst I site (S1 allele). The 222 haplotype was estimated to be pr esent on 48 of the 54 S2-containing chromosomes observed and was assoc iated with increased risk for HTG (relative risk, 3.14; P < 0.0025). T hese results support the existence of apolipoprotein CIII promoter/Sst I haplotypes conferring either protection against or susceptibility t o severe HTG.