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The description of this familial longitudinal cohort was published in this journal 10 years ago, in 1998. To date, 117 publications on the STANISLAS Cohort (SC) have appeared, corresponding to five main categories of results: familial resemblance and heritability; genetics and gene-environment interactions; mRNA and proteins as gene products; reference values and biological variations of proteins; and finally preventive medicine and prepathological epidemiological data. More than 600 data values on demographic and laboratory data have been collected on each individual taking part out of the 1006 families at the beginning and for all three recruitments. Serum and plasma are stored in liquid nitrogen for all participants for all three recruitments. DNA has been extracted from all participants and mRNA from 357 families. They are stored at -80 degrees C. Owing to the SC study, heritability and many gene-environment interactions have been described. The expression of 166 genes related to cardiovascular diseases was measured in peripheral blood mononuclear cells RNA. Reference values for proteins and vitamins have been established in addition to reference values for the carotid and femoral intima media thickness in adults and children. The data obtained contribute to a better understanding of the relation between the studied polymorphisms (161 polymorphic sites) and health, and predisposition to obesity, high blood pressure and metabolic syndrome. To the best of our knowledge, the SC study is internationally the only longitudinal family cohort of subjects who are presumed to be healthy, which enables the study of the chain DNA-RNA-proteins.

Background: The association of genetic profiles with biological or clinical assessments is not clearly established especially among apparently healthy subjects., Methods: A multivariate statistical analysis was performed on 24 polymorphisms related to the main metabolic pathways involved in cardiovascular diseases (CVDs). They were collected among 1551 healthy subjects of the Stanislas cohort to obtain genetic profiles. Association with biological variables was then studied at baseline (t0) and 5 years later (t5)., Results: Six genetic clusters were identified with relevant profiles and five polymorphisms from the selectin, apolipoprotein C3 and lipoprotein lipase genes (SELE-98G/T, APOC3-3175C/G, APOC3-482C/T, APOC3-1100C/T, LPL-93T/G) were sufficiently characteristic to associate 99.6% of the subjects with their corresponding cluster. A 5-year follow-up showed that clinical and biological measurements in relation to CVD risk factors already differ with triglyceride (p=0.009 for t0 and p=0.005 for t5) and high-density lipoprotein cholesterol (p=0.014 for t0 and p=0.003 for t5) for these previous genetic clusters., Conclusions: This study presents the hypothesis that SELE could be protective, whereas APOC3 could be associated with risk. It remains to be seen whether these polymorphisms will be predictive of CVD events among the selected clusters of different metabolic subtypes after a 10-year follow-up.

Laboratory diagnostics has undergone relevant changes in organization and complexity, providing new opportunities and risks. Many laboratory tests are now available on compact, easy to operate and reliable instruments, making it possible for facilities other than the traditional clinical laboratories (e.g., pharmacies) to conduct on-site or mobile testing. Ideally, although there is nothing wrong with a rational decentralization, on-site laboratory testing must still be considered a knowledge service, and a core set of competency-quality-consultancy prerequisites should be fulfilled to ensure that results of tests performed outside the clinical laboratories can reach the highest degree of efficiency and clinical efficacy. Pharmacies were historically involved in clinical chemistry. At the European level, the existing pharmacy syllabus gives to students and postgraduates the physiopathological knowledge a good basis for such an evolution.

Background: Although high-sensitivity C-reactive protein (hs-CRP) has emerged as a cardiovascular marker, questions arise regarding the relative information provided by other inflammatory molecules. Therefore, as a first step, we examined interrelationships between serum hs-CRP concentrations and inflammatory, adhesion and growth factors in healthy adults., Methods: Circulating concentrations of hs-CRP, haptoglobin, orosomucoid, interleukin-6 (IL-6), IL-8, IL-18, tumor necrosis factor-alpha (TNF-alpha), TNF-receptor II (TNF-RII), E-, P-, and L-selectins, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1, endothelial growth factor (EGF), vascular EGF (VEGF), insulin-like growth factor-1 (IGF-1) and IGF-binding protein (IGFBP-3) were measured in 154 men and 161 women of the Stanislas cohort. Leukocyte and platelet counts were also determined., Results: Correlations were significant between hs-CRP concentrations and leukocyte and platelet counts, as well as haptoglobin, orosomucoid, IL-6, and ICAM-1 concentrations (p< or =0.001). Correlation coefficients for ICAM-1 were higher in men than in women (p< or =0.05). When stratifying subjects according to hs-CRP levels, the group with high hs-CRP levels had significantly higher haptoglobin and orosomucoid concentrations than the others, in addition to higher leukocyte counts and IL-6 concentrations in women, and platelet counts and ICAM-1 concentrations in men., Conclusions: Further studies are warranted to explain the association pattern for hs-CRP. Partition of these factors according to their association with hs-CRP concentration opens a new perspective for choice of the best factors in terms of cardiovascular risk in relation to hs-CRP, while non-associated markers could be used to give additional information.

In order to investigate possible ethnic differences in genetic and environmental determinants, we investigated several cardiovascular disease-associated genetic variations in successful ageing populations of France (Nancy) and China (Hong Kong). Allelic frequencies of these genetic variations were compared between healthy elderly Chinese (n=103) and French populations (n=100). A multi-locus assay was used to genotype 15 genes for 29 biallelic sites, genes implicated in lipid and homocysteine metabolism, thrombosis, leukocyte adhesion, and blood pressure regulation. For most of the candidate markers within lipid metabolism genes, the less frequent alleles were more common in the Chinese population compared with the French population, while the less frequent alleles of the majority of the other markers were detected only or more commonly in the French population. In conclusion, polymorphisms in 13 genes exhibited statistically significant differences in allelic frequencies between the two populations. Since the two populations were selected as examples of successful ageing, we could hypothesise that genetic factors that could play a role in a successful ageing process may be different between the two populations.

Insulin is involved in coronary heart disease through diabetes and metabolic syndrome. A great deal is known about insulin and its correlates, as well as factors related to changes in insulin. However, few studies consider the broad variety of correlates simultaneously. Therefore, the aims of the present study were to characterize the main factors of biological variation affecting serum insulin concentration and to establish reference limits of insulinemia in a presumably healthy French population. Insulin was measured using a microparticular enzymatic immunoassay. A total of 646 subjects aged 11-58 years from the STANISLAS cohort and divided into four groups of 162 males, 157 females, 163 boys and 164 girls, were included in the statistical analyses. In the whole population, serum insulin concentration varied from 0.80 to 54.60 microU/ml. Significant factors affecting insulin were age, gender, body mass index and glucose, in addition to alanine aminotransferase and high-density lipoprotein cholesterol in men, triglycerides and oral contraceptive use in women, and alkaline phosphatase in girls. In summary, we presented biological correlates of insulin in both healthy French male and female adults and children/adolescents and determined reference limits for insulin for each group. These results will contribute to a better interpretation of insulin data in further studies and laboratory investigations.

Laboratory tests were at the origin of the modern approach to the evaluation of the health status in many Preventive Medicine Centers. Guided by the theory of reference values and its applications, years of efforts have been devoted to defining the health status of people, and understanding the biological variation of the population. At the Nancy Center for Preventive Medicine, 40,000 people are invited every year for health examination; many coming with their families. French legislation authorized every citizen to have full health examination every five years. Annually, 600,000 people are seen at 70 centers. The visit includes answering questionnaires, physiological and biological testing modified for age, risks, and social criteria. The process concludes with consultation with a general practitioner. Data accumulated over 30 years have led to the identification of primary factors influencing biological variation of common laboratory tests. For example, body mass index (BMI) has to be considered, in addition to age and gender, for measurement of gamma-glutamyltransferase, alanine aminotransferase, and other analytes. More recently, the familial Stanislas cohort has shown that apolipoprotein E (apoE) genetic polymorphism has to be considered as a factor for variation in some individuals. For example, there was greater than 100% difference in the mean concentration of apoE between epsilon2/epsilon2 and epsilon4/epsilon4 individuals. This example nicely illustrates the relationship between genotype and phenotype. Demonstrating the effects of multiple gene polymorphisms on phenotypes will be a valid approach to predictive laboratory medicine.

This study describes the factors of variation of the enzymes related to the PON1-192 phenotype assessment, i.e., basal paraoxonase, salt-stimulated paraoxonase and arylesterase activities, and compares the PON1-192 phenotype to the PON1-192 genotype assessments in supposedly healthy subjects issued from the Stanislas cohort study. The studied population included 918 subjects, i.e., 221 families including 441 adults and 477 children aged 4 to 58 years. Potential determinants such as age, gender, body mass index, alcohol and tobacco consumption, and oral contraceptive intake have been studied. The PON ratio (salt-stimulated paraoxonase/arylesterase) was trimodally distributed and the cut-off values used to differentiate the two homozygous (AA and BB phenotypes) from the heterozygous (AB phenotype) subjects were 3.0 and 7.0 in this study. In males, basal paraoxonase and salt-stimulated paraoxonase activities were not affected by alcohol consumption and current smoking, but basal paraoxonase activity was decreased by 15% by current smoking and was increased by 15% by oral contraceptive intake in females as was the salt-stimulated paraoxonase activity. The level of discordance between phenotype and genotype assessments was 7.2% (66/918). Most of the discrepancies were observed between the BB and AB phenotypes (4.25%).

The variability in drug response originates partly from genetics, with possible consequences for drug efficacy, adverse effects, and toxicity. Until now, pharmacogenetics mainly indicated the best known source of variability, that is, the variability caused by drug metabolism. However, simultaneous progress in the knowledge of biochemical targets of drugs and of the human genome, together with the development of new technologies, revealed many new sources of human genetic variation, e.g., in receptors or transporters. Drugs are metabolized by various polymorphic phase I enzymes, including cytochromes P450 (CYP). Among them, the most relevant for the metabolism of cardiovascular drugs are CYP3A4, CYP2C9 or CYP2C19, and CYP2D6. The role of phase II enzymes is limited with regard to cardiovascular drugs biotransformation, but some polymorphisms (glutathion-S-transferase; GSH-T) are linked to cardiovascular risk. Phase III proteins or transporters, especially from the ABC family, must also be considered, as their polymorphisms affect cholesterol and other sterols transport. Among pharmacological targets, some proteins were identified as involved in interindividual variations in the response to cardiovascular drugs. Some examples are apolipoprotein E, angiotensin-converting enzyme, and the beta-adrenergic receptor. From the risk concept emphasizing impaired metabolism and adverse effects, we now moved to an approach, which is a personalized, genotype-dependent adaptation of therapy.

The aim of this work was to describe the factors influencing the levels of three antioxidant markers -total antioxidant status, erythrocyte copper/zinc superoxide dismutase (SOD), whole-blood selenium glutathione peroxidase--and to establish their reference intervals in supposedly healthy subjects. The studied population included 463 subjects, i.e., 223 adults and 140 children aged 20 to 65 and 4 to 19 years, respectively. The effect of factors such as age, gender, body mass index, alcohol and tobacco consumption, menopause, drug intake, trace elements, transferrin, ferritin, albumin, bilirubin, haptoglobin, total proteins, uric acid, haemoglobin, and mean corpuscular volume of erythrocytes have been studied for the three antioxidant markers. Total antioxidant status (TAS) was higher in men than in women whatever the age (p < 0.001). Albumin and uric acid in men, women and girls, and total proteins in boys were significant determinants of TAS levels. Mean corpuscular volume of erythrocytes were negatively and significantly associated with SOD activity in men and in women (p < 0.01) but not in children. Among the studied determinants, none were found to influence the selenium glutathione peroxidase activity in the four groups. Reference intervals including the 90% confidence intervals were established by age and sex for the three antioxidant markers.

Early epidemiological studies showed that genetic factors contribute to the risk of cardiovascular disease. Genetic epidemiological studies based upon families can be used to investigate familial trait aggregation, to localize genes implicated in cardiovascular diseases in the human genome, and to establish the role of environmental factors. Family studies can be also used to identify the physiological role of candidate genes for cardiovascular diseases, and to characterize shared environmental risk factors and their impact on the expression of genetic predisposition. The present paper reviews the existing family studies with special emphasis on those which have studied healthy populations in relation to cardiovascular disease such as the Framingham Heart Study, the National Heart, Lung, and Blood Institute Family Heart Study, and the STANISLAS cohort.

Myeloperoxidase (MPO) is a glycoprotein released by activated polymorphonuclear neutrophils, which takes part in the defense of the organism through production of hypochlorous acid (HOCl), a potent oxidant. Since the discovery of MPO deficiency, initially regarded as rare and restricted to patients suffering from severe infections, MPO has attracted clinical attention. The development of new technologies allowing screening for this defect has permitted new advances in the comprehension of underlying mechanisms. Apart from its implications for host defense, the expression of MPO restricted to myeloid precursors makes MPO mRNA a good marker of acute myeloid leukemia. In addition, during the last few years, involvement of MPO has been described in numerous diseases such as atherosclerosis, lung cancer, Alzheimer's disease and multiple sclerosis. Both strong oxidative activity and MPO genetic polymorphism have been involved. This review summarizes the broad range of diseases involving MPO and points out the possible use of this protein as a new clinical marker and a future therapeutic target.