ApoCIII gene variants modulate postprandial response to both glucose and fat tolerance tests

Background-We investigated the relationship between variation in the apolip oprotein (apo) AI-CIII-AIV gene cluster and response to an oral glucose tes t (OGTT) and oral fat load test (OFPT) in the EARSII group of young, health y male offspring whose fathers had had a myocardial infarction before the a ge of 55 years (cases, n=407) compared with age-matched controls (n=415). T he apoCIII variations examined were C3238G (SstI) in the 3'-UTR, C1100T in exon 3, C-482T in the insulin response element (IRE), and T-2854G in the ap oCIII-AIV intergenic region. Methods and Results-The postprandial response was regulated by variation at the T-2854G and C3238G sites. After the OFTT, carriers of the rare alleles had delayed clearance of triglyceride (Tg) levels; G-2854 carriers showed the largest effect on Tg (AUC, 24%; greater, P<0.002; peak, 19% greater, P< 0.005), and G3238 carriers showed a smaller response (AUC, 13% greater, P<0 .05; peak, 13% greater, P=0.03). However, after adjustment for fasting leve l of Tg, only the effect with the T-2854G remained significant. Variation a t the C-482T (IRE) determined response to the OGTT, with carriers of the ra re T-482 having significantly elevated glucose (28.7% AUG, P=0.013) and ins ulin (20.5% AUG, P<0.01) concentrations. Conclusions-These data suggest that specific genetic variants at the apoCII I gene locus differentially affect postprandial and response to OGTT and su ggest a novel mechanism for the effects of variation at this locus on risk for atherosclerosis.