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Apolipoprotein D (apoD) is a member of the lipocalin family of proteins. Most members of this family are transporters of small hydrophobic ligands, although in the case of apoD, neither its physiological function(s) nor its putative ligand(s) have been unequivocally identified. In humans, apoD is expressed in several tissues, including the CNS, and its synthesis is greatly increased during regeneration of rat peripheral nerves. As apoD may have an important function in the nervous system and, particularly, in nerve regeneration, we measured immunoreactive apoD levels in the hippocampus and in CSF of patients with either Alzheimer's disease (AD) or other neuropathologies. In parallel, we determined the concentrations of apolipoprotein E (apoE), another apolipoprotein also implicated in nerve regeneration and in the etiology of AD. Levels of apoD but not apoE were increased in the hippocampus of AD patients compared with controls. ApoD concentrations, as determined by radioimmunoassay, were significantly increased in the CSF of AD patients (4.23 ± 1.58 µg/ml) and patients with other pathologies (3.29 ± 1.35 µg/ml) compared with those in the CSF of normal subjects (1.15 ± 0.71 µg/ml). Although the differences were smaller than for apoD, the mean apoE concentrations in the CSF of both groups of patients were also significantly higher than those of controls. In AD patients, apoD, but not apoE, levels in CSF and hippocampus increased as a function of inheritance of the ε4 apoE allele. This study therefore demonstrates that increased apoD levels in the hippocampus and in CSF are a marker of neuropathology, including that associated with AD, and are independent of apoE concentrations.

Sex differences occur before adolescence for arterial diameter, but only at an adult age for intima-media thickness. In young subjects, carotid geometry seems to be influenced by blood pressure and excess body weight, while femoral artery geometry seems to be related to blood pressure and body growth.

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The human apolipoprotein (apo) E gene is polymorphic, with three common alleles (epsilon 2, epsilon 3, epsilon 4) coding for three isoforms (E2, E3, E4). The isoforms differ from each other by a single amino acid substitution, and also differ in their binding affinity for the four apo E receptors. Apo E polymorphism is an important determinant of risk for the development of cardiovascular and Alzheimer diseases, the prevalence of the epsilon 4 allele being increased in both kinds of patients compared with control subjects. Furthermore, the prevalence of the epsilon 4 allele differs among populations (range 5-40%, respectively, for Taiwanese and Papua New Guineans). Genotyping or phenotyping needs to be introduced in clinical laboratories. The choice of the method should be based on the types of patients who are examined. The apo E genotype is also a determinant of apo E plasma concentration. Standardization of apo E measurement is an important prerequisite before investigating the clinical interest of plasma apo E concentration. Determination of apo E genotype/phenotype and later the plasma concentration are expected to yield useful clinical laboratory information.

Summary The mechanisms underlying the variability of factor VIII (FVIII) levels are still poorly understood. The only receptor of FVIII identified so far is the lipoprotein receptor‐related protein (LRP), which is thought to be involved in FVIII degradation. We aimed to characterize biological and genetic factors related to FVIII variability, focusing on coding polymorphisms of the LRP gene and polymorphisms potentially detected by molecular screening of the LRP‐binding domains of the FVIII gene. Plasma FVIII coagulant activity (FVIII:C) and von Willebrand factor (VWF:Ag) antigen levels were measured in a sample of 100 healthy nuclear families (200 parents and 224 offspring). The ABO blood group and the three coding polymorphisms of the LRP gene (A217V, D2080N and C766T) were genotyped. Lipids and anthropometric factors poorly contributed to the variability of FVIII:C (<5%). A strong effect of ABO blood groups on FVIII:C levels was observed that remained significant after adjustment for VWF:Ag levels (P = 0·02). These two factors explained more than 50% of FVIII:C variability. After adjustment for VWF:Ag and ABO blood groups, a residual resemblance for FVIII:C persisted between biological relatives (ρ = 0·13 ± 0·06 between parents and offspring, ρ = 0·24 ± 0·09 between siblings) compatible with an additional genetic influence. The N allele of the LRP/D2080N polymorphism was associated with decreased levels of FVIII:C (90·4 ± 8·7 vs. 102·2 ± 3·5 IU/dl, P = 0·03) and VWF:Ag levels (109·1 ± 11·2 vs. 125·4 ± 4·4 IU/dl, P = 0·02). No polymorphism was detected in the LRP‐binding domains of the FVIII gene. This study reinforces the hypothesis of a genetic influence of FVIII levels beyond the influence of VWF:Ag and ABO blood groups. The D2080N polymorphism of the LRP gene weakly contributed to the variability of FVIII:C levels in this healthy population.

The main objective of the Stanislas cohort is to study the role and the contribution of genetic and environmental factors to cardiovascular status. We plan: a) to describe the degree of association of a large number of cardiovascular risk indicators with cardiovascular endpoints, b) to evaluate the contribution of genetic and that of environmental factors to this association, c) to follow the evolution of these risk indicators during a period of at least ten years, d) to search for the determinants influencing this evolution. The principal variables studied are: a) blood pressure, cardiac mass, and wall thickness of carotid and femoral arteries, b) obesity and fat mass, c) indicators of lipid metabolism, d) genetic polymorphisms of several cardiovascular risk candidate genes, e) food, tobacco and alcohol consumption, f) consumption of drugs and anti-oxidant vitamins. Between September 1993 and August 1995, 1006 families consisting of the two biological parents with at least two children were recruited totalling 4295 individuals. This cohort will be followed up until 2004. There will be two health examinations five and ten years after the initial examination. A bank of blood samples (serum and plasma) in liquid nitrogen and DNA (-80 degrees C) has been established.

Fine-mapping of trait loci through combined linkage and association analysis is an important component of strategies designed to identify causative gene variants, particularly in situations where the trait may be influenced by one or more of many polymorphisms within the same gene. Angiotensin-1 converting enzyme (ACE) provides one of the best models for developing and testing such methodologies, as a major fraction of the heritable variation in the activity of the angiotensin-1 converting enzyme (ACE) is tightly linked to the ACE gene. Moreover, ACE contains many frequent polymorphisms that are in strong linkage disequilibrium with each other. Although none of these variants induces a significant amino-acid change, one or more, either singly or in combination, are likely to have a strong effect on the quantitative phenotype. Here, we show that measured-haplotype analysis of SNP data from a large European family cohort can be used to localise the major ACE-linked genetic factors influencing the trait to a 16 kb interval within the gene, thus limiting the number of ACE variants that need to be considered in future studies designed to elucidate their biological effects. The approaches developed will be applicable to the fine-mapping of other quantitative trait loci in humans.