Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*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.
de Knijff
P
P
Netherlands Organization for Applied Scientific Research, Institute of Prevention and Health Research, Gaubius Laboratory, Leiden.
van den Maagdenberg
A M
AM
Boomsma
D I
DI
Stalenhoef
A F
AF
Smelt
A H
AH
Kastelein
J J
JJ
Marais
A D
AD
Frants
R R
RR
Havekes
L M
LM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000595:Amino Acid Sequence; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D017931:DNA Primers; D005260:Female; D015870:Gene Expression; D006580:Genetic Carrier Screening; D005973:Glutamine; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood / Q000235:genetics*; D008239:Lysine; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction
D053329:Apolipoprotein E2; D001057:Apolipoproteins E; D017931:DNA Primers; D005973:Glutamine; D008239:Lysine