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Apolipoprotein E polymorphism and lipoproteins in insulin-treated diabetes mellitus

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      Abstract

      Apoliproprotein E (apo E), a component of VLDL, HDL and chylomicron remnants, is inherited at a single genetic locus with 3 common alleles (ϵ2, ϵ3 and ϵ4). ϵ2 homozygosity is found in 0–2% of healthy populations, but in 75–100% of subjects with type III hyperlipoproteinaemia, in whom an increased prevalence of glucose intolerance has previously been reported. The lipoprotein abnormality associated with diabetes mellitus has features in common with type III hyperlipoproteinaernia and both conditions lead to accelerated atherogenesis with a similar anatomical distribution. We have therefore examined the frequency of apo E genotypes in 120 subjects with insulin-treated diabetes mellitus (ITDM) and 107 healthy controls, and examined the effect of apo E polymorphism on lipoproteins in the diabetic group. As in the general population, the apo E phenotype in ITDM was a significant determinant of the total serum and LDL cholesterol concentrations which were lowest in patients possessing the ϵ2 allele, intermediate in those homozygous for ϵ3 and highest in those with an e4 allele. The observed gene frequences of ϵ2 (0.091), ϵ3 (0.780) and ϵ4 (0.130) were similar to those of the healthy control group and those in the general population. However, there was an unexpected increase (P < 0.0002) in ϵ2 homozygosity of 6.7% compared to a prevalence of 0.8% predicted both from the Hardy-Weinberg equilibrium and the 0.9% prevalence observed in the healthy control group. This suggests either that ϵ2 homozygosity increases susceptibility to the development of ITDM or that the two conditions are genetically linked. Of the eight ϵ2 homozygotes with diabetes, one expressed the full clinical syndrome of type III hyperlipoproteinaemia and broad β-lipoprotein was also detected in one other. This suggests that the tendency to type III hyperlipoproteinaemia is greater in diabetic than in previously studied non-diabetic ϵ2 homozygotes, although it is not inevitable in the insulin replete patient.
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