Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man

Abstract

PRIMARY dysbetalipoproteinaemia (broad-β disease, hyper-lipoproteinaemia type III) is a familial disorder of plasma lipoprotein metabolism associated with xanthomatosis and early onset of severe atherosclerotic vascular disease^1–4. A defect in the catabolism of triglyceride-rich lipoproteins probably underlies the accumulation of atypical cholesterol-rich lipoproteins (very low density β lipoproteins, ‘β–VLDL’) in the S_f 12–400 density fraction^5–7. The disorder is assumed to be rare⁸ and we have provided evidence for an autosomal recessive mode of inheritance^9,10. Patients show a variant of one major protein component (Apo E) of VLDL^1,12. Apo E is a glycoprotein of molecular weight ∼ 39,000 that splits into three main bands designated E-I (pI∼5.3), E-II (pI∼5.4) and E-III (pI∼5.55) in iso-electric focusing¹³. The Apo E variant is characterised by a deficiency of Apo E-III in triglyceride-rich lipoproteins. We report here that Apo E shows a genetic polymorphism determined by two alleles Apo Eⁿ and Apo E^d. About 1% of the German population is homozygous for the allele Apo E^d and exhibits Apo E-III deficiency. All individuals of this genotype have a primary dysbetalipoproteinaemia but not necessarily hyperlipidaemia. This is therefore the most frequent monogenic dyslipoproteinaemia known in man.