The Relationship Between Vascular Endothelial Growth Factor Cis- and Trans-Acting Genetic Variants and Metabolic Syndrome.

BACKGROUND: We have investigated the association between 4 cis- and trans-genetic variants (rs6921438, rs4416670, rs6993770 and rs10738760) of the vascular endothelial growth factor (VEGF) gene and metabolic syndrome (MetS) and its individual components in an Iranian population. MATERIAL & METHOD: Three hundred and thirty-six subjects were enrolled and MetS was defined according to the International-Diabetes-Federation (IDF) criteria. Genotyping was carried out in all the individuals for 4 VEGF genetic variants using an assay based on a combination of multiplex polymerase chain reaction and biochip array hybridization. RESULTS: As may be expected, patients with MetS had significantly higher levels of serum high-sensitivity C-reactive protein, waist circumference, hip circumference, body mass index, fat percentage, systolic blood pressure, diastolic blood pressure and triglyceride, whereas the high-density lipoprotein cholesterol levels were significantly lower, compared to the control group (P < 0.05). We also found that 1 of the VEGF- level associated genetic variants, rs6993770, was associated with the presence of MetS; the less common T allele at this locus was associated with an increased risk for MetS. This association remained significant after adjustment for confounding factors (P = 0.007). Individuals with MetS carrying the AT + TT genotypes had markedly higher levels of fasting blood glucose, triglyceride and systolic blood pressure (P < 0.05). CONCLUSIONS: We have found an association between the rs6993770 polymorphism and MetS. This gene variant was also associated with serum VEGF concentrations. There was also an association between this variant and the individual components of the MetS, including triglyceride, fasting blood glucose and systolic blood pressure.

Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.

BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. METHODS: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. RESULTS: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. CONCLUSIONS: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.

Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers.

AIM: To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients. METHODS & RESULTS: At 1-month follow-up, the interactions of smoking and CYP2C19 polymorphisms on the vasodilator-stimulated phosphoprotein - platelet reactivity index (VASP PRI), and CRP were explored in three metabolizing groups (1128 patients) as follow: poor metabolizers (*2 carriers/*17 noncarriers); intermediate metabolizers (*2 carriers/*17 carriers or *2 noncarriers/*17 noncarriers); and ultrarapidmetabolizers (*2 allele noncarriers/*17 carriers). The interactions of metabolizing status and smoking was significant for CRP (p = 0.001) but not for VASP PRI (p = 0.734). CONCLUSION: Interaction between CYP2C19 polymorphisms and smoking modifies on-treatment CRP level of post-stenting, on-thienopyridine patients. This effect seems to be independent to the level of P2Y12 receptor inhibition.

Influence of genetic variations on levels of inflammatory markers of healthy subjects at baseline and one week after clopidogrel therapy; results of a preliminary study.

We aimed to assess the association between the most common polymorphisms of cytochrome P450 (CYP) epoxygenases on the plasma levels of inflammatory markers in a population of healthy subjects. We also sought to determine whether CYP2C19 2 polymorphism is associated with the anti-inflammatory response to clopidogrel. In a population of 49 healthy young males, the baseline plasma levels of inflammatory markers including C-reactive protein, haptoglobin, orosomucoid acid, CD-40 were compared in carriers vs. non-carriers of the most frequent CYP epoxygenase polymorphisms: CYP2C9 2, CYP2C9 3, CYP2C19 2, CYP2C8 2 and CYP2J2 7. Also, the variation of inflammatory markers from baseline to 7 days after administration of 75 mg per day of clopidogrel were compared in carriers vs. non-carriers of CYP2C19 allele and also in responders vs. hypo-responders to clopidogrel, determined by platelet reactivity tests. There was no significant association between epoxygenase polymorphisms and the baseline levels of inflammatory markers. Likewise, CYP2C19 allele was not associated with anti-inflammatory response to clopidogrel. Our findings did not support the notion that the genetic variations of CYP epoxygenases are associated with the level of inflammatory markers. Moreover, our results did not support the hypothesis that CYP2C19 2 polymorphism is associated with the variability in response to the anti-inflammatory properties of clopidogrel.

Dairy product consumption, calcium intakes, and metabolic syndrome-related factors over 5 years in the STANISLAS study.

OBJECTIVE: We assessed the associations of total dairy products; milk, yogurt, and cottage cheese; cheese; and calcium with 5-y changes in components of the metabolic syndrome. METHODS: Two hundred eighty-eight men and 300 women 28 to 60 y of age from the suivi temporaire annuel non invasif de la santé des lorrains assurés sociaux (STANISLAS) cohort completed at baseline a 3-d dietary record. Statistics were performed using multivariate regression analysis. RESULTS: In men, no relation was found between the four dietary indices and components of the metabolic syndrome measured at baseline. Conversely, the consumption of milk, yogurt, and cottage cheese at entry was inversely associated with 5-y changes in glucose levels (P ≤ 0.05, P ≤ 0.01 for sex interaction) and positively with 5-y changes in high-density lipoprotein cholesterol (P ≤ 0.05). Higher calcium intakes were significantly related to a lower 5-y increase of the body mass index (BMI) and waist circumference in men (P ≤ 0.01, P ≤ 0.05 for sex interaction). In addition, changes in diastolic blood pressure were inversely associated with the consumption of milk, yogurt, and cottage cheese only in men with a normal BMI (P ≤ 0.05 for BMI interaction). In women, unlike men, associations were shown for some components measured at baseline: total dairy positively related to BMI and waist circumference; total dairy, milk, yogurt, and cottage cheese, and calcium were positively related to triacylglycerols and negatively to high-density lipoprotein cholesterol. However, no significant association was found for any 5-y-changes. CONCLUSION: In men only, a higher consumption of dairy products was associated with positive changes in the metabolic profile in a 5-y period; a higher calcium consumption was associated with a lower 5-y increase of the BMI and waist circumference.

Alcohol Consumption, Beverage Preference, and Diet in Middle-Aged Men from the STANISLAS Study.

The question about differences in dietary patterns associated with beer, wine, and spirits is still unresolved. We used diet data from 423 middle-aged males of the STANISLAS Study. Using adjusted values for covariates, we observed a negative significant association between increasing alcohol intakes and the consumption of milk, yogurt, and fresh/uncured cheese, sugar and confectionery, vegetables and fruits, and a significant positive relationship with cheese, meat and organs, pork-butcher's meat, and potatoes. In addition, the first dietary pattern identified by factor analysis (characterized a more prudent diet) was inversely related to alcohol intakes. Conversely, when analyzing daily consumption of specific food groups and diet patterns according to beverage preference (wine, beer, and spirits), no significant difference was observed. In conclusion, in this sample of middle-aged French males, there was a linear trend between increasing alcohol intakes and worsening of quality of diet, while no difference was observed according to beverage preference.

Clinical necessity of partitioning of human plasma haptoglobin reference intervals by recently-discovered rs2000999.

BACKGROUND: Very recently, we identified a novel polymorphism, rs2000999, located in haptoglobin gene (HP) as a strong genetic determinant of the haptoglobin levels (Hp). We aim to determine the reference values of Hp on the basis of its main sources of biological variation including the rs2000999 in a large French origin population, the STANISLAS Family Study (SFS). METHODS: Through a stepwise regression analysis, the main biological variables of Hp levels were identified in 3129 "apparently" disease-free individuals of the SFS. Hp reference ranges were subsequently established in a subgroup of 2923 selected healthy subjects, as the reference population. RESULTS: The plasma reference values of Hp ranged 0.08-1.97 g/L in males and 0.08-2.19 g/L in females. Gender, age, smoking, plasma levels of hemoglobin and the newly-discovered HP polymorphism, rs2000999, were found to be the strongest biological predictors of the Hp concentrations in human plasma. Hp levels, in both genders and in all age groups, were negatively associated with the presence and number of rs2000999 minor allele. CONCLUSION: To be reliably interpretable in daily medical practice, the HP polymorphism, rs2000999, should be considered for partitioning its reference values. This polymorphism may also help for setting decision limits for medical interpretation of Hp concentrations.

A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (ß = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

High prevalence of metabolic syndrome in Iran in comparison with France: what are the components that explain this?

BACKGROUND: The aim of this study was to investigate the difference in the prevalence of metabolic syndrome and its components between an Iranian and a French population. METHODS: The prevalence of metabolic syndrome, defined according to the Adult Treatment Panel III (ATP III), and of related abnormalities, was estimated in 1,386 French and 1,194 Iranian adults. RESULTS: The prevalence of metabolic syndrome was significantly higher in Iranian women (55.0%), followed by Iranian men (30.1%), than in French men (13.7%) and French women (6.6%). Iranian women were characterized by high rates of abdominal obesity (65.0%), hypertension (52.1%), hypertriglyceridemia (43.1%), and low high-density lipoprotein cholesterol (HDL-C; 92.7%). Iranian men were characterized by high rates of hypertension (48.9%), hypertriglyceridemia (42.8%), and low HDL-C (81.8%). French men had high rates of hypertension (44.7%) and mild rates of hypertriglyceridemia (28.6%) and hyperglycemia (23.9%). There was a relationship between waist circumference and the lipid components of metabolic syndrome in both countries. CONCLUSION: The main finding of this study is the high prevalence of low HDL-C concentrations in the Iranian population, especially in Iranian women, compared with French women. Explanation of this observation could help in establishing prevention strategies.

Human formyl peptide receptor 1 C32T SNP interacts with age and is associated with blood pressure levels.

BACKGROUND: Human formyl peptide receptor 1 (FPR1) mediates inflammatory responses, recognized as important participants in the physiopathology of hypertension. Similarly, FPR1 C32T SNP is associated with inflammation and BP related pathways. Therefore, the relationship between FPR1 C32T SNP, BP and hypertension needs to be investigated. METHOD: 1012 French middle-aged adults including 491 healthy individuals (5 years follow-up, T(+0) and T(+5)) and 521 hypertensive individuals were PCR-RFLP genotyped for FPR1 C32T SNP (rs5030878). RESULTS: At entrance, there was no significant association between FPR1 C32T SNP and blood pressure (BP) in healthy individuals. However, 5 years later, significant associations were found for DBP, SBP (p<0.001 and p=0.009 respectively) and for their 5 years changes (Δ) (p=0.025 and p=0.027 for DBP and SBP respectively). Significant interactions between FPR1 C32T SNP and age on DBP, SBP, ΔDBP and ΔSBP were found (p=0.014, 0.008, 0.015 and 0.015 respectively). Consequently, stronger increase in BP was reported among healthy individuals aged less than 45 years. When normotensive individuals were compared to hypertensives ones, similar FPR1 C32T genotypes and allele frequency distributions were found. CONCLUSION: FPR1 C32T SNP interacts with age, is associated with higher and a 5 years increase of BP levels in healthy individuals aged less than 45 years.

Klotho KL-VS genotype is involved in blood pressure regulation.

BACKGROUND AND AIMS: Genome-wide linkage analysis studies reported the importance of the long arm of chromosome 13 in systolic blood pressure regulation. Therefore, isolating a genetic variant related to this chromosomal region could be challenging. Klotho KL-VS allele is located on this chromosomal region and its relationships with cardio-vascular risk factors need extensive investigations. The aim of the present study is to examine whether the klotho KL-VS genotype is associated with cardio-vascular risk factors, more particularly hypertension, in two independent cohorts. A secondary objective was to investigate relationships with antihypertensive treatment, arterial stiffness and carotid artery parameters. METHODS AND RESULTS: A total of 1023 French individuals were genotyped for klotho KL-VS. Participants were part of the French ERA and STANISLAS cohorts. In both cohorts, klotho KL-VS/KL-VS genotype was significantly associated with lower systolic blood pressure and pulse pressure when compared to homozygous and heterozygous more frequent (WT) allele carriers (p=0.003 and p<0.001 respectively). Antihypertensive treatment stratification confirmed the previous significant associations, while a significant interaction between klotho KL-VS genotype and antihypertensive treatment was also interestingly found (0.019 for p interaction). CONCLUSION: Klotho KL-VS/KL-VS genotype may be associated with decreased cardio-vascular risk and may interact with antihypertensive treatment in order to reduce blood pressure. This finding could lead to identify subgroups of hypertensive adults who might benefit antihypertensive drug therapies.

Biological and genetic factors associated with ABCB1 and pregnane-X-receptor expressions in peripheral blood mononuclear cells in the STANISLAS cohort.

BACKGROUND: ABCB1 is a membrane transporter ubiquitously expressed particularly in peripheral blood mononuclear cells (PBMCs). Resistance to drugs is associated with genetic variations of its gene and with modulation of its expression through the pregnane-X-receptor (PXR) transcription factor. We have previously shown that ABCB1 polymorphisms were associated with blood lipid concentrations. METHODS: We wanted to investigate the variation factors and the genetic determinants of ABCB1 and PXR expressions in PBMCs, and their interrelationships with plasma lipid levels. ABCB1 and PXR mRNA were quantified by real-time quantitative RT-PCR in PBMCs of 42 men and 39 women. RESULTS: ABCB1 and PXR were both expressed in PBMCs of all individuals, but their expressions were not significantly correlated. ABCB1 mRNA was correlated with body mass index (BMI; p=0.01) and age (p=0.03). In women, lymphocyte count also correlated with ABCB1 transcripts (p<0.01). After adjustment for BMI, correlation with age disappears. PXR mRNA expression depends on gender with men expressing higher PXR levels (p=0.01). PXR expression also correlates with γ-glutamyltransferase (GGT; p=0.02), but this disappeared after adjustment. CONCLUSIONS: Neither ABCB1 nor PXR expressions correlate with ABCB1 gene variants. Finally, association between ABCB1 or PXR expression in PBMCs and lipid or apolipoprotein plasma concentrations were not significant in this subset of healthy subjects. These results should be confirmed in a larger population sample and extended to patients with various cardiovascular risk profiles.

Metabolic syndrome-related composite factors over 5 years in the STANISLAS family study: genetic heritability and common environmental influences.

BACKGROUND: We estimated genetic heritability and common environmental influences for various traits related to metabolic syndrome in young families from France. METHODS: At entrance and after 5 years, nineteen traits related to metabolic syndrome were measured in a sample of families drawn from the STANISLAS study. In addition, 5 aggregates of these traits were identified using factor analysis. RESULTS: At entrance, genetic heritability was high (20 to 44%) for plasma lipids and lipoproteins, uric acid, fasting glucose, and the related clusters "risk lipids" and "protective lipids". Intermediate or low genetic heritability (less than 20%) was shown for triglycerides, adiposity indices, blood pressure, hepatic enzyme activity, inflammatory makers and the related clusters: "liver enzymes", "adiposity/blood pressure" and "inflammation". Moreover, common environmental influences were significant for all the parameters. With regard to 5-year changes, polygenic variance was low and not statistically significant for any of the individual variables or clusters whereas shared environment influence was significant. CONCLUSIONS: In these young families, genetic heritability of metabolic syndrome-related traits was generally lower than previously reported while the common environmental influences were greater. In addition, only shared environment contributed to short-term changes of these traits.

Sex-dependent associations of leptin with metabolic syndrome-related variables: the Stanislas study.

Serum leptin has been reported to be associated in a sex-dependent manner with C-reactive protein (CRP), independently of adiposity. We tested the hypothesis that leptin is associated, independently of anthropometry indexes and in a sex-dependent way, with other inflammatory markers and variables related to metabolic syndrome (MS). In 384 healthy middle-aged adults (192 men and 192 women) total fat mass (FM), waist circumference (WC), serum leptin and 15 MS-related parameters (systolic and diastolic blood pressure, triglycerides, cholesterol, high density lipoprotein (HDL)-cholesterol, apo AI and B, fasting glucose, uric acid, CRP, orosomucoid and haptoglobin levels and aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities) were measured. After adjustment for age, alcohol and cigarette consumption, WC, and total FM, leptin concentration was significantly associated with serum triglycerides, total cholesterol, apo B, uric acid and haptoglobin concentrations and liver enzyme activity only in men, and with apo AI, HDL-cholesterol (only borderline) and CRP only in women. Sex interaction terms were significant for total cholesterol, apo B, HDL cholesterol, uric acid, ALAT and GGT, and borderline significant for triglycerides, apo AI and ASAT. In this healthy population, leptin is significantly associated with various MS factors, independently of WC and total FM, depending on gender. Our study provides further evidence of sex-related differences mediated by leptin in inflammatory mechanisms and other MS-related metabolic pathways.

Human formyl peptide receptor 1 (FPR1) c.32C>T SNP is associated with decreased soluble E-selectin levels.

AIMS: The human formyl peptide receptor (FPR) is a G protein-coupled chemoattractant receptor that is thought to mediate inflammatory responses. The FPR1 gene is highly polymorphic. In a recent study, the FPR1 c.32C>T SNP, resulting in the amino-acid substitution I11T, was reported to be significantly associated with C-reactive protein levels. Therefore, this study sought to determine if the impact of such a genetic variation extends to other clinical parameters associated with inflammation, including cytokines, adhesion molecules and inflammatory markers. MATERIALS & METHODS: This study was carried out on a subsample of 325 adults selected from the STANISLAS cohort study. The FPR1 c.32C>T SNP was genotyped using PCR amplification followed by restriction enzyme digestion. Anthropometric measurements and biochemical profiles were assessed for each individual. RESULTS: The allele frequencies of FPR1 c.32C>T were 0.74 for the 32C allele and 0.26 for the 32T allele. Genotype frequencies were 0.55 for C/C, 0.38 for C/T and 0.07 for T/T. After adjusting for age, sex, BMI, alcohol and cigarette consumption, oral contraceptive, antibiotics and anti-inflammatory drug use, statistical analysis (under a recessive model of inheritance) demonstrated that serum E-selectin levels were 68% lower in individuals homozygous for T/T than in those with C/T or C/C genotypes (p = 0.001). However, no significant correlations were found for C-reactive protein or the other 18 tested clinical parameters that were analyzed in this study. CONCLUSION: The FPR1 c.32C>T SNP may be associated with E-selectin levels in the French population. Although of importance, these findings need confirmation in larger studies.

Association between EGF and lipid concentrations: a benefit role in the atherosclerotic process?

CONTEXT AND OBJECTIVE: Previous in vitro studies have shown a relationship between epidermal growth factor (EGF) and lipid metabolism. Indeed, EGF is able to modulate lipoprotein fractions in human fetal intestine and hepatic-derived cell lines. The aim of this study was to search for potential associations between EGF concentrations and lipid parameters in both plasma and peripheral blood mononuclear cells (PBMCs) among healthy individuals. DESIGN: EGF concentrations were quantified in plasma of 273 men and 279 women and in PBMCs of 57 men and 62 women from the STANISLAS cohort. In addition, basic blood constituents including lipid parameters (apolipoproteins A1, and B, total and high-density lipid (HDL)-cholesterols and triglycerides) were measured. RESULTS: Plasma EGF concentrations were significantly and positively correlated with apolipoprotein A1 and HDL-cholesterol concentrations after adjustment for age, sex, and body mass index (r=0.155, P=0.0003; and r=0.112, P=0.0086, respectively). They were also negatively correlated with the apolipoprotein B/A1 ratio (r=-0.107, P=0.012). In addition, EGF concentrations in PBMCs were negatively correlated with apolipoprotein B, total and low-density lipid-cholesterols, and triglyceride concentrations, and apolipoprotein B/A1 ratio (P=0.0018, P=0.0137, P=0.0142, P=0.0162, and P=0.0077, respectively, with r ranging between -0.287 and -0.222). No interactions were found with gender. CONCLUSION: New associations between EGF and lipid concentrations have been reported, providing new perspectives with regard to the role of EGF in atherosclerosis.

Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural tube defects: a multicenter case-control study.

Neural tube defects (NTDs) are severe congenital malformations due to failure of neural tube formation in early pregnancy. The proof that folic acid prevents NTDs raises the question of whether other parts of homocysteine (Hcy) metabolism may affect rates of NTDs. This French case-control study covered: 77 women aged 17-42 years sampled prior to elective abortion for a severe NTDs (cases) and 61 women aged 20-43 years with a normal pregnancy. Plasma and erythrocyte folate, plasma B6, B12 and Hcy were tested as five polymorphisms MTHFR 677 C --> T, MTHFR 1298 A --> C, MTR 2756 A --> G, MTTR 66 A --> G and TCN2 776 C --> G. Cases had significantly lower erythrocyte folate, plasma folate, B12 and B6 concentrations than the controls, and higher Hcy concentration. The odds ratio was 2.15 (95% CI: 1.00-4.59) for women with the MTRR 66 A --> G allele and it was decreased for mothers carrying the MTHFR 1298 A --> C allele. In multivariate analysis, only the erythrocyte folate concentration (P = 0.005) and plasma B6 concentration (P = 0.020) were predictors. Red cell folate is the main determinant of NTDs in France. Folic acid supplement or flour fortification would prevent most cases. Increased consumption of vitamins B12 and B6 could contribute to the prevention of NTDs. Genetic polymorphisms played only a small role. Until folic acid fortification becomes mandatory, all women of reproductive age should consume folic acid in a multivitamin that also contains B12 and B6.

[Preanalytical variations of proteic biomarkers]. / Variations pré-analytiques des biomarqueurs protéiques.

In the area of proteomic, results of analysis were for a long time dependant on analytical variations. Nowadays, due to the emergence of new technologies and controls of data, these variations are less important than those due to preanalytical conditions, which are difficult to overcome. The reasons are due to the number of parameters and to the fact that the biologist is not always fully informed. In this document, we present the main preanalytical factors of variation, and their effects on the results of analysis. New technologies involving mass spectrometry are very promising, but they are very sensitive to parameters like the stability of samples and the choice of the clotting agent. Thus, it is more and more necessary to take these data into account.

Association of classical and related inflammatory markers with high-sensitivity C-reactive protein in healthy individuals: results from the Stanislas cohort.

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.

Heritability for plasma VEGF concentration in the Stanislas family study.

Vascular endothelial growth factor (VEGF), a key regulator of blood vessel function during angiogenesis, has been related to various diseases including atherosclerosis, neurodegenerative disorders and cancers. However, data about genetic determinants of its concentration in blood are scarce. The present study aimed at estimating additive genetic heritability, household component effect and the influence of 3 common VEGF polymorphisms on plasma VEGF concentration. A random sub-sample of 160 nuclear families (647 individuals), aging from 5 to 57, was obtained from the Stanislas Family Study. Plasma VEGF concentration was measured by a multiplexing ELISA and genotyping of the polymorphisms C(-460)T, G(405)C and C(936)T of the VEGF gene was carried out by RFLP. After adjustment for the influence of known environmental covariates, significant familial correlations were observed for plasma VEGF concentration (P< or = 0.01 and P< or = 0.001) for all the various pairs of relatives, except between spouses. In addition, variance component analysis showed no significant household common environment contribution to variability of this trait, while the genetic contribution accounted for 60.6% regardless of the 4 classes of relatives. Taking the three polymorphisms into account did not modify the variance components. These results show that plasma VEGF concentrations are under genetic control in healthy families and that none of the 3 candidate polymorphisms significantly altered heritability.