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Apolipoprotein E2 isoform in patients with CAD
Thursday I3 October 1994: Poster Abstracts Apolipoprotein E
with apo E through this mechanism to become a better ligand for the hepatic CR receptor. This may also be a pathway for the enrichment or remodeling of circulating lipoproteins with cell surface-associated apoproteins, including apo E and A-I.
El m,
Apolipoprotein E2 isoform in patients with CAD Kw&niak M, Zdzienicka A, Hartwich J, Kruszelnicka-Kwiatkowska 0*, Piwowarska W, Dembidska-KieC A,
Dept. of Clin. Biochem, *Clinic of Coronary Disease, Coilegium Medicum, Jagiellonian Universiry, Cracow, Poland
Genetic polymorphism of apo E is associated with atherosclerosis. With the prospect of introducing apo E phenotyping into the study of risk factors for CAD we asked whether and when analysis of apo E phenotype will provide additional predictive information. Two groups of men were studied: group I, 70 men with angiographically documented CAD and group II, 70 male volunteers with no clinical or ECG signs of coronary insufficiency. In CAD patients, the apo E3/2 phenotype was significantly more frequent than in group II, the apo E4/2 was present whereas it was absent from group II, and the incidence of all apo E2 isoforms was over twice as high as in the controls. There was no difference in apo E2 incidence between men in the two groups if they had a normal lipid profile, normal or impaired glucose tolerance or hypercholesterolemia. A higher incidence of apo E2 isoform was found only in CAD patients (3-4 times more frequent than in non-CAD subjects) when the common feature was hypertriglyceridemia or hyperinsulinemia. The study confirms the relation between apo E/2 and apo E4/2 and the appearance of CAD, and suggests that early detection of the apo E2 isoform may identify subjects with hypertriglyceridemia or hyperinsulinemia who are at higher risk of development of CAD. Probing structure and function of VLDL by synthetic 1101 amphipathic peptides $&t&E& Palgunachari MN, Mishra VK, Chang R, Anantharamaiah GM, Atherosclerosis Res. Unit, Dept. of Med., UAB Medical Center, Birmingham, AL. 35294, USA
We have studied the effect of interaction of three peptide analogs of the amphipathic helix with VLDL on the structure and function of VLDL. The three analogs are: (1) 18 residue peptide possessing a single helical domain (18A) with the sequence D-W-LK-A-FY-D-K-V-A-E-K&K-E-A-F, (2) two domains of 18A separated by a Pro (18A-P-18A or 37pA) and (3) an 18A analog with the end group protected to increase helicity (AC-18A-NH& All three peptides, when incubated with VLDL at a peptide:VLDL (protein) ratios of 1: 1, are able to displace most of apo E and/or apo Cs from VLDL; the rank order of the ability of the three peptide analogs to displace apo E and/or Cs was AC-18A-NH2 > 37pA > 18A. Apo E was more readily displaceable by peptides than apo Cs; apo C-111swere more readily displaceable than apo C-II. The peptide-treatment also enhanced the dissociation of albumin from VLDL. The peptide treatment variably affected the potencies of VLDL to interact with purified lipoprotein lipase (LPL) and cultured macrophages: AC-18A-NH2 treatment of VLDL markedly lowered the reactivity of VLDL to LPL and the ability of VLDL to induce lipid accumulation in cultured macrophages, but 18A or 37pA interaction with VLDL affected its potencies only minimally. The loss of reactivity of Ac-18A-NHZ-treated VLDL was only partially restored when ah the displaced apolipoproteins were included in the lipolysis mixture. Studies of the interaction of artificial lipid emulsion with LPL and pancreatic phospholipase A showed that 37pA, but not AC-18A-NH2, can serve as an activator of LPL and enhance the hydrolytic activity of phospholipase
263
A. This study demonstrates that apo E is the most readily displaceable apolipoprotein species of VLDL, that full activation of LPL by apo C-II requires the binding of apo C-II to VLDL, and that treatment of VLDL with peptides having the same sequence and arranged to possess differences in structure, have significantly different effects on the properties of VLDL, which indicates that apolipoprotein structure and not sequence is important for VLDL function. Differences in genetic variation of apolipoprotein E in I Lapps and Finns Luoma P, Lehtimiiki T, Nayha S, Hassi J, Nikkari T, J.&&,& Dept. of Biochemistry, Inst. of Biomedical Sciences, Tampere. Box 607, SF 33101 Tampere, Finland
Univ. of
The Lapps are the oldest population in the northern patt of Fennoskandia. There are 50 000-75 000 Lapps in Fennoskandia, and 4000-6000 of them live in Finland. The area where Lapps live was already inhabited 10 000 years ago, but their origin is unknown. In several populations, the apolipoprotein E (apo E) allele ~4 is associated with high concentration of plasma TC and LDL-C and increased risk of coronary artery disease (CAD). The structural gene for apo E is polymorphic, with three codominant alleles, ~2, ~3 and ~4. These alleles code for three apo E isofotms E2, E3 and W, respectively. The expression of any two of these three alleles results in six plasma apo E phenotypes: EU2, E3/2, E4/2, E3/3, E4/3 and E4/4. The purpose of this study was to compare the apo E allele frequencies in the Lapps and the Finns, and to relate the apo E phenotypes to plasma TC and LDL-C levels. The apo E phenotypes from 70 Lappish (both parents Lapps) and 210 Finnish mindeerherdsmen were determined by isoelectric focusing and Western blotting. The apo E allele frequencies in Lapps vs Finns were &2,5% vs 3%; ~3, 64% vs 79%; ~4, 31% vs 181, respectively. The differences between these two populations were statistically significant k2-test, P = 0.006). The TC and LDL-C levels in the Lapps were higher than in the Finns, but the difference was not statistically significant (P > 0.05). TC and LDL-C levels increased in both the Lapps and the Finns according to apo E phenotype in the order of E3/2, E4/2, E3/3, E4/3 and E4/4, but the difference was not statistically significant (P > 0.05). The results suggest that the Lapps differ genetically from the Finns. The Lapps have more apo E allele ~4 than any other studied population. Despite the increased risk for CAD reported to be associated with this allele, the morbidity in CAD in Lapps is lower than in other parts of Finland. The explanation for this might be found in some protecting factor in the genotype, lifestyle or environment of the Lapps. Serum apolipoprotein (a) levels and apolipoprotein E 1 polymorphism in middle-aged men wR, Vtiisiinen S, Rankinen T, Htttltiinen E, Hakulinen P, Ryynanen M, Kuopio Research Inst. of Exercise Med., Puistokatu 20, FIN-70110 Kuopio
The aim of the study was to analyze the association between serum ape(a) levels and apo E polymorphism in two populationbased cohorts of Eastern Finnish men (n = 302) aged 50-60 years. Serum ape(a) level was determined by radioimmunoassay and apo E genotype by a polymerase chain reaction combined with the detection of single base changes in the amplified gene fragment with solid-phase minisequencing (first cohort) or by restriction fragment length polymorphism method (second cohort). The median (95% CI) of the ape(a) was 151 U/l (106; 180). The number of subjects with E2J3 genotype was 28, E3/3 genotype 184 and E2/4, E3/4 or E4/4 genotype 90. Age, waist to hip ratio, and cholesterol in serum, VLDL and HDL fractions as well serum apolipcproteins A-I, A-II and B and serum insulin levels
Atherosclerosis X, Montreal, October 1994
with apo E through this mechanism to become a better ligand for the hepatic CR receptor. This may also be a pathway for the enrichment or remodeling of circulating lipoproteins with cell surface-associated apoproteins, including apo E and A-I.
El m,
Apolipoprotein E2 isoform in patients with CAD Kw&niak M, Zdzienicka A, Hartwich J, Kruszelnicka-Kwiatkowska 0*, Piwowarska W, Dembidska-KieC A,
Dept. of Clin. Biochem, *Clinic of Coronary Disease, Coilegium Medicum, Jagiellonian Universiry, Cracow, Poland
Genetic polymorphism of apo E is associated with atherosclerosis. With the prospect of introducing apo E phenotyping into the study of risk factors for CAD we asked whether and when analysis of apo E phenotype will provide additional predictive information. Two groups of men were studied: group I, 70 men with angiographically documented CAD and group II, 70 male volunteers with no clinical or ECG signs of coronary insufficiency. In CAD patients, the apo E3/2 phenotype was significantly more frequent than in group II, the apo E4/2 was present whereas it was absent from group II, and the incidence of all apo E2 isoforms was over twice as high as in the controls. There was no difference in apo E2 incidence between men in the two groups if they had a normal lipid profile, normal or impaired glucose tolerance or hypercholesterolemia. A higher incidence of apo E2 isoform was found only in CAD patients (3-4 times more frequent than in non-CAD subjects) when the common feature was hypertriglyceridemia or hyperinsulinemia. The study confirms the relation between apo E/2 and apo E4/2 and the appearance of CAD, and suggests that early detection of the apo E2 isoform may identify subjects with hypertriglyceridemia or hyperinsulinemia who are at higher risk of development of CAD. Probing structure and function of VLDL by synthetic 1101 amphipathic peptides $&t&E& Palgunachari MN, Mishra VK, Chang R, Anantharamaiah GM, Atherosclerosis Res. Unit, Dept. of Med., UAB Medical Center, Birmingham, AL. 35294, USA
We have studied the effect of interaction of three peptide analogs of the amphipathic helix with VLDL on the structure and function of VLDL. The three analogs are: (1) 18 residue peptide possessing a single helical domain (18A) with the sequence D-W-LK-A-FY-D-K-V-A-E-K&K-E-A-F, (2) two domains of 18A separated by a Pro (18A-P-18A or 37pA) and (3) an 18A analog with the end group protected to increase helicity (AC-18A-NH& All three peptides, when incubated with VLDL at a peptide:VLDL (protein) ratios of 1: 1, are able to displace most of apo E and/or apo Cs from VLDL; the rank order of the ability of the three peptide analogs to displace apo E and/or Cs was AC-18A-NH2 > 37pA > 18A. Apo E was more readily displaceable by peptides than apo Cs; apo C-111swere more readily displaceable than apo C-II. The peptide-treatment also enhanced the dissociation of albumin from VLDL. The peptide treatment variably affected the potencies of VLDL to interact with purified lipoprotein lipase (LPL) and cultured macrophages: AC-18A-NH2 treatment of VLDL markedly lowered the reactivity of VLDL to LPL and the ability of VLDL to induce lipid accumulation in cultured macrophages, but 18A or 37pA interaction with VLDL affected its potencies only minimally. The loss of reactivity of Ac-18A-NHZ-treated VLDL was only partially restored when ah the displaced apolipoproteins were included in the lipolysis mixture. Studies of the interaction of artificial lipid emulsion with LPL and pancreatic phospholipase A showed that 37pA, but not AC-18A-NH2, can serve as an activator of LPL and enhance the hydrolytic activity of phospholipase
263
A. This study demonstrates that apo E is the most readily displaceable apolipoprotein species of VLDL, that full activation of LPL by apo C-II requires the binding of apo C-II to VLDL, and that treatment of VLDL with peptides having the same sequence and arranged to possess differences in structure, have significantly different effects on the properties of VLDL, which indicates that apolipoprotein structure and not sequence is important for VLDL function. Differences in genetic variation of apolipoprotein E in I Lapps and Finns Luoma P, Lehtimiiki T, Nayha S, Hassi J, Nikkari T, J.&&,& Dept. of Biochemistry, Inst. of Biomedical Sciences, Tampere. Box 607, SF 33101 Tampere, Finland
Univ. of
The Lapps are the oldest population in the northern patt of Fennoskandia. There are 50 000-75 000 Lapps in Fennoskandia, and 4000-6000 of them live in Finland. The area where Lapps live was already inhabited 10 000 years ago, but their origin is unknown. In several populations, the apolipoprotein E (apo E) allele ~4 is associated with high concentration of plasma TC and LDL-C and increased risk of coronary artery disease (CAD). The structural gene for apo E is polymorphic, with three codominant alleles, ~2, ~3 and ~4. These alleles code for three apo E isofotms E2, E3 and W, respectively. The expression of any two of these three alleles results in six plasma apo E phenotypes: EU2, E3/2, E4/2, E3/3, E4/3 and E4/4. The purpose of this study was to compare the apo E allele frequencies in the Lapps and the Finns, and to relate the apo E phenotypes to plasma TC and LDL-C levels. The apo E phenotypes from 70 Lappish (both parents Lapps) and 210 Finnish mindeerherdsmen were determined by isoelectric focusing and Western blotting. The apo E allele frequencies in Lapps vs Finns were &2,5% vs 3%; ~3, 64% vs 79%; ~4, 31% vs 181, respectively. The differences between these two populations were statistically significant k2-test, P = 0.006). The TC and LDL-C levels in the Lapps were higher than in the Finns, but the difference was not statistically significant (P > 0.05). TC and LDL-C levels increased in both the Lapps and the Finns according to apo E phenotype in the order of E3/2, E4/2, E3/3, E4/3 and E4/4, but the difference was not statistically significant (P > 0.05). The results suggest that the Lapps differ genetically from the Finns. The Lapps have more apo E allele ~4 than any other studied population. Despite the increased risk for CAD reported to be associated with this allele, the morbidity in CAD in Lapps is lower than in other parts of Finland. The explanation for this might be found in some protecting factor in the genotype, lifestyle or environment of the Lapps. Serum apolipoprotein (a) levels and apolipoprotein E 1 polymorphism in middle-aged men wR, Vtiisiinen S, Rankinen T, Htttltiinen E, Hakulinen P, Ryynanen M, Kuopio Research Inst. of Exercise Med., Puistokatu 20, FIN-70110 Kuopio
The aim of the study was to analyze the association between serum ape(a) levels and apo E polymorphism in two populationbased cohorts of Eastern Finnish men (n = 302) aged 50-60 years. Serum ape(a) level was determined by radioimmunoassay and apo E genotype by a polymerase chain reaction combined with the detection of single base changes in the amplified gene fragment with solid-phase minisequencing (first cohort) or by restriction fragment length polymorphism method (second cohort). The median (95% CI) of the ape(a) was 151 U/l (106; 180). The number of subjects with E2J3 genotype was 28, E3/3 genotype 184 and E2/4, E3/4 or E4/4 genotype 90. Age, waist to hip ratio, and cholesterol in serum, VLDL and HDL fractions as well serum apolipcproteins A-I, A-II and B and serum insulin levels
Atherosclerosis X, Montreal, October 1994