VARIABLE EXPRESSION OF FAMILIAL DYSBETALIPOPROTEINEMIA IN APOLIPOPROTEIN E(ASTERISK)2(LYS146-]GLN) ALLELE CARRIERS

Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with familial dysbetalipoproteinemia (FD) carrying the APOE*2 (Lys146-->Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2(Lys146-->Gln) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89+/-0.37 vs 0.30+/-0.27 and 1.86+/-0.37 vs 0.68+/-0.27 mmol/liter, respectively) and plasma apolipoprotein (apo)E levels (28.1+/-1.6 vs 4.6+/-1.1 mg/dl), which is characteristic for FD. By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2(Lys146-->Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lys146-->Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects.