The results of this study indicate that the ACE I/D and β-FG T148C combination may result in significantly higher risk of IS in this Chinese population.
Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3' (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins.
Apolipoprotein E1-Hammersmith (Lys146-->Asn;Arg147-->Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia.
Compound heterozygotes for a novel mutation, apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with severe type III hyperlipoproteinemia and familial hypercholesterolemia.
ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG-rich lipoprotein remnant particles; this isoform is associated with Type-III hyperlipoproteinemia.
All 34 subjects, most of whom displayed clinical or biochemical features of type III hyperlipoproteinemia, were found to be homozygous for apo E2(Arg158----Cys), strongly suggesting that this variant is the most common form of apo E2 within this ethnic and clinical population.
We propose that the single base deletion in the apo E gene which is the cause of a non-functional 'null' allele in addition to a probably dominant apo E1 (Gly127-->Asp, Arg158-->Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.
The mutation at residue 142 decreased the binding activity of apoE to both heparin and the monoclonal antibody 1D7 (this antibody inhibits receptor binding of apoE), whereas apoE2(Arg158----Cys), which is associated with recessive expression of type III hyperlipoproteinemia, binds normally to both.
In all studied populations the receptor-binding defective apo E2 (arg158----cys) is associated with low cholesterol and apo B in heterozygotes and results in primary dysbetalipoproteinemia or type III hyperlipoproteinemia in homozygotes.
This explains the significant effect of the apoE gene locus on the variability of plasma lipoprotein concentrations and moreover the implication of apoE alleles in the aetiology of multifactorial forms of hyperlipidaemia e.g. familial type III hyperlipidaemia (apoE2; arg158----cys) and polygenic hypercholesterolaemia (apoE4; cys112----arg).
We conclude that FD is a genetically heterogeneous disease entity, displaying a recessive mode of inheritance with strongly reduced penetrance in case of the common E2(arg158----cys) variant and with a dominant mode of inheritance with high penetrance in case of the rare E2(lys146----gln) mutant.
These results suggest that, in contrast to the by far most frequently occurring E2(Arg158----Cys) allele, heterozygosity for this uncommon E2 allele may cause familial dysbetalipoproteinemia.
The second, carrying both the rare isoforms apoE1(Gly127-->Asp, Arg158-->Cys) and apoE3(Cys112-->Arg, Arg251-->Gly), presented a hypertriglyceridaemia at the age of 10.3.
It is not yet clear, however, if the hypertriglyceridemia observed in the proband is associated with the presence of the E1(Gly127----Asp, Arg158----Cys) variant.
Family studies failed to demonstrate cosegregation between the new mutations and severe hyperlipoproteinemia, although a number of carriers for the APOE*3(Cys112-->Arg; Arg251-->Gly) allele and the APOE*1(Arg158-->Cys; Leu252-->Glu) allele expressed hypertriglyceridemia and/or hypercholesterolemia.
We assessed, in the Quebec City population, the allele frequency and haplotype distributions of mutations in genes related to HTG, such as the apolipoprotein E (APOE) (C112R and C158R), the apolipoprotein CIII (APOC3) (C-482T and C3238G) and the peroxisome proliferator-activated receptor alpha (PPARalpha) (L162V) genes.
Further, in contrast to reports from other investigators, we found little evidence for association of a C677T polymorphism in the 5,10-methylenetetrahydrofolate reductase gene, the angiotensin-I-converting enzyme 1 insertion/deletion polymorphism, a 4G/5G polymorphism in the serine/cysteine proteinase inhibitor-clade E-member 1 gene, the factor V Leiden mutation, the G20210A factor II mutation, a -455G>A polymorphism in the beta-fibrinogen gene, the cys112arg/arg158cys apolipoprotein E gene polymorphism, a gly460trp polymorphism in the alpha-adducin gene, and a -629C>A polymorphism in the cholesteryl ester transfer protein gene with risk of MI.