Elsevier

Atherosclerosis

Volume 152, Issue 2, October 2000, Pages 475-488
Atherosclerosis

Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project

https://doi.org/10.1016/S0021-9150(99)00501-8Get rights and content

Abstract

As part of the ApoEurope Project, the apolipoprotein E (apo E) serum concentration and polymorphism were determined in 6934 healthy subjects aged 25–64 years recruited in six European countries: Finland; France; Greece; Northern Ireland; Portugal and Spain. Age and sex influenced apo E concentration with concentrations being significantly higher in men than in women for those aged between 25 and 44 years. The age effect differed between the sexes after the age of 44 years, displaying a linear increase in women and a plateau in men. As expected, the serum apo E concentration was highest in ε2 carriers and lowest in ε4 carriers in each country with a significantly higher frequency of the ε4 allele in the northern regions. The main finding of this study was a clear increasing North–South gradient in serum apo E concentration independent of age, sex and apo E genotype. In subjects aged <45 years and with the ε3/ε3 genotype, apo E concentration was higher in the South-East (Greece) as compared to the North by 20% for men and 32% for women. In addition to the genetic polymorphism, the geographical area is an important factor to take into account when studying serum apo E concentration in multicentre studies and defining reference values.

Introduction

Apolipoprotein (apo) E is an important component of plasma lipoproteins and influences lipoprotein metabolism through its action as a receptor ligand. Other important roles of apo E include immunomodulation and nerve regeneration. Apo E is polymorphic with three common alleles: ε2, ε3 and ε4 [1]. More recently polymorphisms in the promoter region have been described [2], [3]. The serum apo E concentration and cholesterol concentration are in part determined by the common apo E polymorphism; thus the ε2 allele is associated with lower serum cholesterol and higher apo E concentration, whereas the ε4 allele is associated with a high serum cholesterol and low apo E concentration [4]. A number of studies [5], [6] have demonstrated that the ε4 allele is associated with an increased risk of coronary artery disease (CAD). It is unclear whether this effect is mediated through the effect of the apo E genotype on lipids or through other mechanisms [7]. Furthermore, the different rates of CAD observed in European countries may partly been explained by the prevalence of apo E genotypes. The role of the apo E serum concentration as a risk factor for CAD has not been investigated.

During recent years several studies have demonstrated that apo E genotype is a determinant of susceptibility to Alzheimer's disease (AD) with ε4 homozygotes at increased risk (for review see [1]). This finding has provided important clues to the pathogenesis of AD. The role of the apo E serum concentration as a risk factor for AD has been studied but the results have been controversial [8], [9]. A prerequisite for the proper investigation of serum apo E concentrations as a risk marker is an understanding of the factors determining serum apo E concentration in health and the establishment of serum reference values

The ApoEurope Project, supported by the European Community, consists of three parts: part I, epidemiology of apo E concentration; part II, role of apo E in cardiovascular disease; part III, role of apo E in Alzheimer's disease. The specific objectives of this paper (part I of ApoEurope) are: (a), to describe the distribution of the serum apo E concentration across different European populations; (b), to study some factors affecting interindividual variation in serum apo E concentration: apo E genotype, age, sex, and geographical area; and (c), to provide apo E genotype related values for serum apo E concentration in four European regions. For these purposes, six research units were selected for collaboration.

Section snippets

Geographical distribution of the sampling locations

Subjects were selected in different geographic areas of Europe for participation in the ApoEurope Project (Part I). In four centres existing databases were used and in two centres new data were collected. Six centres participated: Crete (Greece); Helsinki (Finland); Belfast (Northern Ireland); Nancy (France); Lisbon (Portugal); and Barcelona (Spain). Four European regions were individualized: (a), North (Finland and Northern Ireland); (b), Middle (France); (c), South (Portugal and Spain); and

Population description

The population sample stratified by age, sex, and centre, is presented in Table 1. The contribution of each centre to the total population sample was 7.6% in Greece, about 9–10% in Portugal and Northern Ireland, and 15% in Spain. It reached 28% in France and 30% in Finland. Forty-seven point five percent of all young men, 25–34 years old, came from the Belfast cohort; a majority of males and females 35–44 years old, came from the French cohort (representing 50.5 and 54.3%); 52–60% of the

Discussion

The measurement of serum apo E concentration is, at present, rarely used in clinical chemistry as compared to the use of apo AI and B determinations. The apo E concentration is determined in part by the genetic variation at the apo E locus; however, a large amount of variability remains unexplained by this genetic factor, suggesting that other genetic and environmental components are major determinants of serum apo E concentration. This paper deals with the study of the influence of the apo E

Acknowledgments

We are grateful to all the participants for their contribution in recruitment and the collection of data of the ApoEurope Project. Special thanks to all subjects who made this study possible. This work was supported by the Région Lorraine, Daiichi Pure Chemicals and, by the European Community: contract no. BMH4-1543 (DG 126SSMA) and contract S.M.&T: MAT1-CT94-0046.

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