Cytokines are involved in the development of several inflammatory diseases and atherosclerosis. Their variations in healthy individuals are not well defined. The aims of this study were: firstly, to identify factors affecting biological variation of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-a); secondly, to study their family resemblance; and thirdly, to evaluate the effect of two TNF-a (À308G/A and À238G/A) and two IL-6 polymorphisms (174G/C and À572G/C) on their corresponding circulating levels. A total of 171 healthy families selected from the STANISLAS cohort were studied. Age was negatively related to TNFa concentrations in offspring only (both sons and daughters). Additionally, IL-6 and TNF-a levels were differently influenced by gender, white blood cells, tobacco consumption, and HDL-cholesterol level. A weak significant familial resemblance for TNF-a concentration was observed in siblings only. There was no significant familial resemblance for IL-6 levels. The TNF-a À308A allele was associated with decreased TNFa concentrations in both offspring aged less than 18 and males without overweight (BMIo25 kg/m 2 ). Fathers carrying the IL-6 À174CC genotype had higher IL-6 levels than those with the IL-6 À174G allele. Parents with the IL-6 À572GG genotype had higher IL-6 concentrations than the C allele carriers. In this sample of healthy families, plasma levels of IL-6 and TNF-a were differently affected by biological parameters including age, gender and smoking, and the impact of their respective polymorphisms was influenced by gender, age and BMI.

OBJECTIVE -The purpose of this study was to estimate the longitudinal variation of prevalence of metabolic syndrome within French families and to observe biological parameters involved in cardiovascular disease among their offspring.RESEARCH DESIGN AND METHODS -Three hundred seventy-one apparently healthy families (1,366 individuals) taken from the STANISLAS cohort were studied. The subjects were examined at two time points with a 5-year interval (t 0 and t ϩ5 ). The crude prevalence of metabolic syndrome was assessed among parents according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP) definition.RESULTS -The prevalence of metabolic syndrome was 5.9% in men and 2.1% in women at t 0 , rising to 7.2 and 5.4% in men and women, respectively, at t ϩ5 . Children of parents having metabolic syndrome showed higher levels of tumor necrosis factor-␣ (TNF-␣), whereas their HDL cholesterol and apolipoprotein (apo) E concentrations were lower compared with those of age-and sex-matched control subjects (P Յ 0.05). When applying NCEP ATP definitions that included either antihypertensive drugs only or all the drugs involved in metabolic syndrome, we found that the three parameters shared by the three different versions of the definition were TNF-␣, HDL cholesterol, and an interaction between alcohol consumption and parental metabolic syndrome on HDL cholesterol concentration.CONCLUSIONS -Metabolic syndrome increases with age in supposedly healthy families from the STANISLAS cohort. In offspring of affected people, it seems to be predictive of higher values of TNF-␣ and low HDL cholesterol levels, which are two major cardiovascular factors. Therefore, in terms of prevention, it is important to identify and follow subjects with metabolic syndrome as well as their offspring, even in apparently healthy populations, to enable early disease management. Diabetes Care 28:675-682, 2005

No abstract

Familial hypercholesterolaemia is a genetic disorder characterised by high low-density lipoprotein (LDL) cholesterol concentrations, which frequently gives rise to premature coronary artery disease (CAD). The clinical expression of familial hypercholesterolaemia is highly variable even in patients carrying the same LDL receptor gene mutation. This variability may be due to environmental and other genetic factors. Apolipoprotein E (Apo-E) has been extensively studied for its effects on the phenotype of familial hypercholesterolaemia. In this study we examined the influence of Apo-E genotype on lipid parameters and the incidence of CAD in 93 Greek patients with familial hypercholesterolaemia. Apo-E E2, E3 and E4 allele frequencies were 0.06, 0.86 and 0.09 respectively. The levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins A and B and lipoprotein alpha did not differ significantly among carriers and non-carriers of the E4 allele. The prevalence of CAD and hypertension did not differ either. Our results suggest that the E4 allele is not associated with lipid levels or with the prevalence of CAD among familial hypercholesterolaemia patients of the Greek population.

No abstract

There are a total of 17 families of drugs that are used for treating the heterogeneous group of cardiovascular diseases. We propose a comprehensive pharmacogenomic approach in the field of cardiovascular therapy that considers the five following sources of variability: the genetics of pharmacokinetics, the genetics of pharmacodynamics (drug targets), genetics linked to a defined pathology and its corresponding drug therapies, the genetics of physiologic regulation, and environmental-genetic interactions. Examples of the genetics of pharmacokinetics are presented for phase I (cytochromes P450) and phase II (conjugating enzymes) drug-metabolizing enzymes and for phase III drug transporters. The example used to explain the genetics of pharmacodynamics is glycoprotein IIIa and the response to antiplatelet effects of aspirin. Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome. The examples of cytochrome P450s, APOE and ADRB2 in relation to ethnicity, age and gender are presented to describe genetics of physiologic regulation. Finally, environmental-genetic interactions are exemplified by CYP7A1 and the effects of diet on plasma lipid levels, and by APOE and the effects of smoking in cardiovascular disease. We illustrate this five-tiered approach using examples of cardiovascular drugs in relation to genetic polymorphism.

Atrial natriuretic peptide (ANP or NPPA) is the precursor protein of the form of amyloidosis called isolated atrial amyloid (IAA), which is related to the increased incidence of cardiac pathological conditions with age. Familial hypercholesterolemia (FH) patients are characterized by high concentrations of low-density lipoprotein cholesterol (LDL-C), which frequently gives rise to premature coronary artery disease (CAD). However, not all FH patients have the same clinical phenotype. The aim of the present study was to assess the relationship between ANP polymorphisms and apolipoprotein (Apo) A1 levels and CAD risk in FH patients. Transition T2238C, which leads to ANP with two additional arginines, and G664A (Val7Met) were investigated with lipid values and clinical phenotype in 83 FH patients. ApoA1 and HDL cholesterol levels were lower in GA patients compared to GG homozygotes for the G664A polymorphism. No association was found between the G664A polymorphism and CAD in our population. Moreover, ApoA1 and high-density lipoprotein cholesterol (HDL-C) levels did not differ among the different genotypes of the T2238C polymorphism, even after adjusting for age and sex. The 664A allele of the ANP polymorphism is associated with lower levels of ApoA1 and HDL-C in FH patients, but not with CAD risk. Concerning the T2238C polymorphism, no effect was found on lipid parameters or CAD incidence.

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.