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A number of chronic diseases, including cardiovascular disease, appear to have a multifactorial genetic risk component. Consequently, techniques are needed to facilitate evaluation of complex genetic risk factors in large cohorts. We have designed a prototype assay for genotyping a panel of 35 biallelic sites that represent variation within 15 genes from biochemical pathways implicated in the development and progression of cardiovascular disease. Each DNA sample is amplified using two multiplex polymerase chain reactions, and the alleles are genotyped simultaneously using an array of immobilized, sequence-specific oligonucleotide probes. This multilocus assay was applied to two types of cohorts. Population frequencies for the markers were estimated using 496 unrelated individuals from a family-based cohort, and the observed values were consistent with previous reports. Linkage disequilibrium between consecutive pairs of markers within the apoCIII, LPL, and ELAM genes was also estimated. A preliminary analysis of single and pairwise locus associations with severity of atherosclerosis was performed using a composite cohort of 142 individuals for whom quantitative angiography data were available; evaluation of the potentially interesting associations observed will require analysis of an independent and larger cohort. This assay format provides a research tool for studies of multilocus genetic risk factors in large cardiovascular disease cohorts, and for the subsequent development of diagnostic tests.

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Mutations in the translated part of the leptin gene (LEP) have been found in only two families. Nevertheless DNA polymorphisms in the LEP region are linked to extreme obesity. We previously found in the 5' region of LEP a polymorphism, G-2548A, associated with a differerce in BMI reduction following a low calorie diet in overweight women. Recently, this polymorphism was associated with extreme obesity in women. In this work, we genotyped a new sample from the general population including 314 normal weight (BMI < 27 kg/m2) and 109 overweight subjects (BMI > or = 27 kg/m2). The genotype and allele frequencies were significantly different between groups, with the G-2548 allele being more frequent in the overweight subjects (p < 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass (p = 0.05). Our results indicate that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.

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Human cystatin C is a low molecular weight protein which has been proposed as a better marker of glomerular filtration rate than creatinine. To be able to interpret results obtained in different patient populations it is necessary to define cystatin C reference values. We measured serum concentration of cystatin C in 1223 subjects using a particle-enhanced nephelometric assay. Subjects were aged 4 to 79 years and were selected among apparently healthy individuals who came to the Centre for Preventive Medicine in Vandoeuvre-Lès-Nancy, France. We observed a Gaussian distribution of cystatin C concentration in serum. We did not find any effect of age or gender in children, hormonal status in women (puberty, menopause, oral contraceptives or hormone replacement therapy) or alcohol intake. Cystatin C concentration was slightly lower in female than in male adults below the age of 60 years. Cystatin C levels significantly increased above the age of 60 in both males and females, probably due to physiological aging of renal function. No other significant differences were observed between males and females. Using multiple regression analysis, moderate correlations were observed between body mass index and cystatin C, and between smoking and cystatin C, but these were not biologically significant. According to the literature, only methylprednisolone and cyclosporin A increased and decreased cystatin C levels, respectively. The reference values for cystatin C obtained in a carefully selected population were 0.75+/-0.089 mg/l for children aged 4-19 years, 0.74+/-0.100 mg/l for males and 0.65+/-0.085 mg/l for females (aged 20-59 years), and 0.83+/-0.103 mg/l for older individuals (> or =60 years).

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.