Sophia Visvikis

The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe

Interindividual variation in the concentration of plasma lipids which are associated with coronary artery disease (CAD) risk is determined by a combination of genetic and environmental factors. This study investigates the effects of apoE genotype and plasma concentration on cholesterol and triglycerides (TG) levels in subjects from five countries: Finland, France, Northern Ireland, Portugal, and Spain. Age and sex significantly influenced serum cholesterol, TG and apoE concentrations. The age effect differs in males and females. The allele frequencies of the apoE gene, one of the most widely studied CAD susceptibility genes, were determined: the ε2 allele frequency and the apoE concentration showed a north–south increasing gradient while the ε4 allele frequency showed the reverse. ApoE plays an important role in lipid metabolism. Total cholesterol and TG concentrations were significantly dependent on apoE genotype in both sexes. These differences in lipids between genotypes were more pronounced when plasma apoE concentrations were taken into account.

An insertion deletion polymorphism in the signal peptide of the human apolipoprotein B gene.

SummaryIn this communication we report the genetic properties of an insertion/deletion polymorphism in the signal peptide of the human apolipoprotein B (apo b) gene. There are two alleles of the apo B signal peptide; one codes for a peptide 27 amino acids in length and the other a peptide only 24 amino acids in length. Using the polymerase chain reaction the difference of nine nucleotides between the two alleles is readily detectable after electrophoresis of the amplification products. The relative frequencies of the Ins and Del alleles are 0.655 and 0.345, respectively. The apo B signal peptide genotypes are transmitted in a manner consistent with an autosomal codominant mode of inheritance with two alleles.

Apolipoprotein B signal peptide polymorphism in patients with myocardial infarction and controls

We report the allele frequencies of the apolipoprotein B (Apo B) signal peptide polymorphism in patients with myocardial infarction and compare them with controls. The first sample consists of 197 myocardial infarction patients and 168 controls from Belfast (UK). The second sample consists of 167 myocardial infarction patients and 205 controls from Strasbourg (France), and the third consists of 71 patients and 146 controls from Haute-Garonne (Toulouse, France). No significant differences were observed in the frequency distribution of genotypes among cases and controls or between populations. However, there were more rare homozygotes in the Belfast cases. Significant associations were observed between the Apo B signal peptide polymorphism and mean levels of total cholesterol, low density lipoprotein cholesterol, Apo B and lipoprotein particles containing Apo (a) [Lp(a)] in the Strasbourg control population. Individuals homozygous for the rare allele had higher levels of these lipid parameters. In Belfast, although not statistically significant, the Apo B signal peptide polymorphism had a similar effect on Apo-B-related parameters as seen in Strasbourg. No significant associations were observed in the Haute-Garonne population where the risk of myocardial infarction is three times lower than in Belfast. In all three populations, the average Lp(a) levels were consistently different among Apo B signal peptide genotypes. These data implicate the Apo B signal peptide in determining some of the risks of myocardial infarction in these populations. Regardless of the exact mechanism, the Apo B signal peptide is an important candidate locus for the study of potentially atherogenic lipid variants.

DNA polymorphisms of human apolipoprotein A‐IV gene: frequency and effects on lipid, lipoprotein and apolipoprotein levels in a French population

Genetic polymorphisms of apolipoprotein (apo) A‐IV have been shown to influence lipoprotein metabolism in some human populations. In this study, we have evaluated the physiological effect of three apo A‐IV polymorphisms (Gln360‐ < His, Thr347‐ < Ser and XbaI within the second intron of the apo A‐IV gene), in a French population, on seven quantitative traits: total cholesterol and triglycerides, cholesterol of HDL, apo A‐IV, apo B, apo A‐I and glucose. The polymorphism at amino‐acid 360 was determined by direct analysis of polymerase chain reaction products. The allele frequencies were 0.92 for the A‐IV1 and 0.08 for the A‐IV2 allele. The genetic polymorphism at codon 347 was investigated by allele‐specific oligonucleotide hybridization. The allele frequencies of the two alleles, A‐IV347Thr and A‐IV347Ser, were 0.78 and 0.22, respectively. The XbaI polymorphism was investigated by polymerase chain reaction followed by XbaI restriction enzyme digestion of the amplified products. The frequencies of the two apo A‐IV alleles, XbaI‐1 and XbaI‐2, were 0.79 and 0.21, respectively. None of the three apo A‐IV polymorphisms had a significant effect on lipoprotein, apolipoprotein and glucose levels.

Signal Peptide–Length Variation in Human Apolipoprotein B Gene: Molecular Characteristics and Association with Plasma Glucose Levels

We studied the molecular characteristics of three naturally occurring variants in the human apolipoprotein B (apoB) signal peptide, their frequencies in non-insulin-dependent diabetic and random populations, and their association with several measures of lipid and carbohydrate metabolism. In a random sample of 197 French whites, there were two common alleles, 5′βSP-24 and 5′βSP-27, with frequencies of 0.35 and 0.65, respectively. In a random sample of 181 Mexican Americans, there was an additional allele, 5′βSP-29, with a frequency of 0.03. DNA sequence analysis indicated that the signal peptide alleles consisted of the following: 5′βSP-29 encoded 29 amino acids in the signal peptide containing two copies of the sequence CTG GCG CTG encoding Leu-Ala-Leu and a consecutive run of eight Leu-encoding codons; 5′βSP-27 encoded 27 amino acids with a run of only six Leu codons; 5′βSP-24 encoded 24 amino acids and contained a single copy of CTG GCG CTG and a run of six Leu codons. In the sample of French whites, average apoAI and glucose levels were significantly different among signal peptide genotypes. 5′βSP-24/24 homozygotes had higher apoAI levels than the two other signal peptide genotypes (1.59 vs. 1.42 g/L, respectively). Heterozygous 5′βSP-24/27 individuals had the highest glucose levels. In the random sample of Mexican Americans, average glucose levels were also significantly different among signal peptide genotypes. However, the rank order of average glucose levels was not the same between the two samples. In the sample of Mexican Americans, glucose levels were significantly elevated (6.14 mM) in the 5′βSP-24/24 homozygotes relative to the other genotypes. Correspondingly, average glycosylated hemoglobin levels were increased and C-peptide levels were decreased in homozygous 5′βSP-24/24 individuals. There were no significant differences in the frequency of the three signal peptide alleles between the random sample of Mexican Americans and a sample of 203 non-insulin-dependent diabetic Mexican Americans. The cause of the association (e.g., chance, linkage-phase disequilibrium, causation) between signal peptide–length variation and plasma glucose levels is not known.

Frequency and effects of the apolipoprotein A‐IV polymorphism

Plasma from 158 presumed healthy nuclear families has been analyzed by high‐resolution, two‐dimensional electrophoresis to study the frequency and effects of the genetic polymorphism in human apolipoprotein A‐IV. Two common alleles, apo A‐IV 1 and apo A‐IV 2 were detected with relative frequencies of 0.943 and 0.057, respectively. Autosomal codominant transmission of these two alleles coded for by a single structural locus was demonstrated. Furthermore, we studied the effects of this apo A‐IV variability on total plasma cholesterol, triglyceride, glucose levels and gamma‐glutamyltransferase activity. Statistically significant differences among apo A‐IV genotypes for the average glucose level were detected. The average effect of the apo A‐IV 1 allele was to lower plasma glucose levels by 0.013 mmol/l, whereas the average effect of the apo A‐IV 2 allele was to raise glucose levels by 0.213 mmol/l.

Lipid and lipoprotein genetic variability: An important contribution from the French health Examination Centers☆

OBJECTIVEnTo assess lipid and lipoprotein genetic variability in the French Population.nnnMETHODSnMany health examination centers are covering a great part of France (700,000 individuals are examined in 54 centers every year). Each citizen has the right to have a personal examination every 5 years. This unique system was modified in 1992, and we are presenting our 25-year experience focusing on the results we have more recently obtained in the lipid and lipoprotein field.nnnRESULTSnFirst of all, the 600 items of information collected on every patient coming to our Center give us the data and facilitate the development of the theory of reference values. Having mastered the analytical variations, we studied the biological variations. Age, sex, overweight, tobacco, alcohol, and drugs are the main factors we should control for obtaining reference values. More recently, the genetic part in the production of reference values has become of greater importance, particularly for apolipoproteins. Apolipoprotein E is an important lipoprotein for which the two frequent mutations influence the level of circulating Apolipoprotein E. The risks linked to these alleles are also very different in cardiovascular disease and extremely important (for epsilon 4) in Alzheimers Disease. Apolipoproteins B and A-IV also have interesting polymorphisms, but currently have no systematic applications in clinical chemistry. The familial recruitment we have in Nancy also permitted us to constitute a large tool La Cohorte Stanislas.nnnCONCLUSIONnThe thousand families recruited will be followed for 10 years. It is an open tool for collaboration.