Apolipoprotein E and complement C3 polymorphism and their role in the response to gemfibrozil and low fat low cholesterol therapy.

Three different allelic variants of apolipoprotein E determine, in concert with other gene products, the levels of plasma lipoproteins. Recently, cleavage products of the complement C3 molecule have also been implicated in determining plasma triacylglycerol concentrations. This study presents data of an ongoing study to dissect the role of the apolipoprotein E gene locus in the response to low fat/low cholesterol diet combined with gemfibrozil treatment. In addition, for the first time, the significance of C3 allelic variants to such hypolipidaemic therapy response was analysed. To this end data from 81 obese hyperlipoproteinaemic patients (Fredrickson type II/A and B and type IV and V) confirmed the usefulness of the combined gemfibrozil/diet treatment and unveiled apolipoprotein E allele group specific therapy responses. The mean changes of lipid properties due to combined treatment was 15% for total cholesterol, 48% for triacylglycerols and 28% for atherogenic index. Division into hyperlipidaemia types according to Fredrickson and subgrouping into E2, E3 and E4 groups (apolipoprotein E2/2 and 2/3, apolipoprotein E3/3 and apolipoprotein E4/2 and 4/3 phenotype groups respectively) exposed pronounced differences from these mean changes, suggesting substantial influence of apolipoprotein E variants on this therapy. We observed triacylglycerol reductions of from 17% in type IIA-apolipoprotein E3 group patients up to 78% in the type IV and V-apolipoprotein E2 group. Thus it might be concluded the apolipoprotein E genotyping aides therapy success prediction. Although, low sample number in some subgroups obscures significance in this pilot study, significant therapy success emerges for the E3 and E4 group in type IV and V hyperlipidaemia and type IIB-apolipoprotein E3 homozygous patients can be predicted to respond better than apolipoprotein E2 carriers. Finally, we present evidence that positive changes of lipid properties are also determined by the "fast" complement C3 allel (C3-F). Patients with complement factor C3-FS pattern respond better to treatment than patients with C3-SS configuration. In summary these data endorse the genotyping of apolipoprotein E alleles to predict maximal success of "fibrate" treatment. In addition they argue strongly for further assessment of the involvement of complement C3 allelic variations in lipid homeostasis.