Biomedical subjects

C Pallaud

Publications and source records attributed to C Pallaud.

11 recordsLinked to original sources

PubMed2001

Sample size calculations for classical association and TDT-type methods using family data.

Transmission Disequilibrium Test (TDT)-based methods have been advocated by several authors for testing that a marker-phenotype association is actually due to linkage and not to uncontrolled stratification. As a pre-requisite of TDT-type methods is the presence of an association between marker and phenotype, one may wish to first investigate the association using a classical association study, and then to check by a TDT approach whether this association is actually due to linkage. We propose an estimating equation (EE) procedure, to compute analytically the minimum sample size of sibship data required to detect the association between a marker and a quantitative phenotype, and that required to confirm it by two TDT methods. We show that, when the marker allele frequency is low or high, the number of informative sibs needed in TDT-type methods can be lower than the number required in an association analysis, and even more so when the familial clustering is strong. However, in all cases, the number of sibs that need to be sampled to get the appropriate number of informative sibs for analysis is always larger for TDT methods than for an association study. In a phenotype-first strategy, this number may be critical when investigating costly phenotypes.

Alleles↗

PubMed2001

APOC3, CETP, fibrinogen, and MTHFR are genetic determinants of carotid intima-media thickness in healthy men (the Stanislas cohort).

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) inter-individual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B-mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French Cohort: the Stanislas Cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analyses were carried out by ANOVA, after adjustment of CIMT for age, body mass index, and smoking, and by multiple regression analyses. No association was found with APOB Thr71Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T, and SELE Ser128Arg, polymorphisms neither in men nor in women. Although, in women we did not find any association for APOC3 3206T/G, 3175C/G, 1100C/T, CETP Ile405Val, MTHFR 677C/T and fibrinogen -455G/A polymorphisms; in men these polymorphisms were associated with CIMT variability (p< or =0.01; p< or =0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability.

Adult↗

PubMed2001

Candidate gene polymorphisms in cardiovascular disease: a comparative study of frequencies between a French and an Italian population.

A multilocus assay was used to genotype up to 27 variable sites in 15 genes in French and Italian, presumed to be healthy populations (n=1480, n=162, respectively). These genes are involved in lipid metabolism (APOE, APOB, APOC3, CETP, LPL, PON), homocysteine metabolism (CBS, MTHFR), blood viscosity (Fibrinogen, FV), platelet aggregation (GpIIIa), leukocyte adhesion (SELE), and renin-angiotensin system (AT1R, ACE, AGT). Allele frequencies for all the markers were compared between the two populations. Five allele frequencies differed between the two European countries: APOB 71Ile (p < 0.001), SELE 98T (p < 0.001), SELE 128Arg (p < or = 0.01), APOE E4 (p < or = 0.01) and MTHFR 677T (p < or = 0.01), suggesting the existence of a north-south gradient in European allele frequencies. The other allele frequencies : APOC3 -482T, -455C, 1100T, 3175G, 3206G; LPL -93G, 9Asn, 291Ser; CETP 405Val; PON 192Arg; ACE Del; AGT 235Thr; AT1R 1166C; CBS 278Thr, GpIIIa P1A2; Fibrinogen -455A, FV 506Gln and SELE 554Phe, were similar between the two populations. They were also similar to those observed in other European countries.

Alleles↗

PubMed2001

[APOC3, CETP, beta-fibrinogen and MTHFR are genetic determinants of carotid intim-media thickness (Stanislas cohort)].

The purpose of this study was to examine the relationship between carotid intima-media thickness (CIMT) interindividual variability and 16 polymorphisms of 11 genes associated with cardiovascular risk factors (genes among lipid and homocysteine metabolisms, blood viscosity, platelet aggregation, leukocyte adhesion and renin-angiotensin system). CIMT was measured by high resolution B mode ultrasonography in an healthy population of 77 men and 84 women, aged 35-54 years and selected from a French cohort: the Stanislas cohort. The polymorphisms studied were genotyped by a multilocus approach. Statistical analysis were done by ANOVA after adjustment of CIMT for age, BMI and smoking and by multiple regression analyses. No association was found with APOB Thr71 Ile, APOC3 -482C/T, -455T/C, GpIIIa P1A, AT1R 1166A/C, AGT Met235Thr, CBS Ile278Thr, SELE 98G/T and SELE Ser128Arg, polymorphism neither in men nor in women. Although, in women we found always no association for the APOC3 3206T/G, 3175C/G, 1100C/T, the CETP Ile405Val, the MTHFR 677C/T and the fibrinogen -455G/A polymorphism's, in men these polymorphism's were associated with CIMT variability (0.01 < or = p < or = 0.05). The most interesting finding was that altogether these genes in men were able to explain a considerable part, 20.6%, of CIMT variability. Therefore, our study gives a new opportunity to understand CIMT variability.

Adult↗

PubMed2001

[Association between E-selectin Leu554Phe polymorphism and blood pressure in the Stanislas cohort].

We investigated the relationship between polymorphisms of the E-selectin gene, SELE (L/F554, S/R128 and 98G/T), a cell adhesion molecule, and interindividual variability in blood pressure and changes over time. The study population was extracted from the Stanislas Cohort (1006 families), a cohort of nuclear families volunteering for a free health check-up and recruited by the Centre of Preventive Medicine in Nancy (CMP) between 1993 and 1994. For this specific study, 359 men and 337 women were selected from families that had already visited the CMP 11 years before the recruitment of the Stanislas Cohort. Measurements of blood pressure at the time -11 years (t-11) and at the time of recruitment (t0), and all other measurements necessary for the analysis (BMI, lipids, SELE genotypes) were available. Pregnant women or subjects taking antihypertensive, lipid lowering or anti-inflammatory medications were excluded from the study. During the follow-up period, systolic and diastolic blood pressure (SBP and DBP) were lower in SELE F554 allele carriers than in those with the L/L554 genotype (p < or = 0.05), whereas longitudinal changes were not related to any SELE polymorphism. Multiple regression analysis showed that at t-11 SELE L/F554 polymorphism was associated with both SBP and DBP levels (p < or = 0.01 and p < or = 0.05, respectively). However, these associations were no longer present at t0. Our results suggest an age-specific effect of the SELE L/F554 polymorphism on blood pressure levels. If confirmed in other studies, these findings would suggest that assessment of common variation in an adhesion molecule could be useful in predicting blood pressure.

Adult↗

PubMed2001

Genetic influences on lipid metabolism trait variability within the Stanislas Cohort.

The contribution of 17 polymorphisms within 13 candidate genes on lipid trait variability was investigated by a multiplex assay in 772 men and 780 women coming for a health checkup examination. The studied genes were APOE, APOB, APOC3, CETP, LPL, PON, MTHFR, FGB, GpIIIa, SELE, ACE, and AGT. We found that APOB-Thr71Ile, APOE-(112/158), APOC3-1100C/T, and SELE-98G/T polymorphisms had a significant effect on lipid traits (P < or = 0.001 to P < or = 0.01). Genetic effects accounted for 3.5-5.7% of variation in apolipoprotein B (apoB)-related traits among men, and for 5.7-9.0% among women. The contribution of APOE polymorphism on apoB-related traits variability was two to three times more important in women than in men. We found suggestive evidence for interactive effects between genetics and age, smoking status, and oral contraceptives. Increase of LDL-cholesterol and apoB concentrations with age was stronger among the epsilon4 carriers in women, and apolipoprotein A-I (apoA-I) concentration decreased with age in epsilon4 male carriers. The effect of epsilon2 allele on LDL-cholesterol was more important in the oral contraceptive users. In nonsmokers only, the APOC3-1100C allele in women was related to lower apoB-related traits concentrations, and in men to higher apoA-I and HDL-cholesterol concentrations. In conclusion, this work, in addition to the reinforcement of the already known associations between APOB, APOE, and APOC3 genes and lipids, leads to new perspectives in the complex relationships among genes and environmental factors. The newly observed relationships between E-selectine gene and lipid concentrations support the hypotheses of multiple metabolic pathways contributing to the complexity of lipids variability.

Adult↗

PubMed2000

Relationship between E-selectin L/F554 polymorphism and blood pressure in the Stanislas cohort.

We investigated the relationship between polymorphisms of the E-selectin gene SELE (L/F554, S/R128 and 98G/T), a cell adhesion molecule, and interindividual variability in blood pressure and changes over time. The study population was extracted from the Stanislas cohort (1006 families), a cohort of nuclear families volunteering for a free health check-up and recruited by the Center of Preventive Medicine in Nancy (CMP) between 1993 and 1994. For this specific study 359 men and 337 women were selected from families who had already visited the CMP 11 years before recruitment of the Stanislas Cohort. Measurements of blood pressure 11 years before (t(-11)) and at the time of recruitment (t(0)), and all other measurements necessary for the analysis (body mass index, lipids, SELE genotypes) were available. Pregnant women or subjects taking antihypertensive, lipid-lowering, or anti-inflammatory medications were excluded from the study. During the follow-up period systolic and diastolic blood pressures were lower in SELE F554 allele carriers than in those with the L/L554 genotype (P<0.05), but longitudinal changes were not related to any SELE polymorphism. Multiple regression analysis showed that at t(-11) SELE L/F554 polymorphism was associated with both systolic and diastolic blood pressure levels (P<0.01 and P<0.05, respectively). However, these associations were no longer present at t(0). Our results suggest an age-specific effect of the SELE L/F554 polymorphism on blood pressure levels. If confirmed in other studies, these findings would suggest that assessment of common variation in an adhesion molecule could be useful in predicting blood pressure.

Adult↗

PubMed2000

Familial studies on the genetics of cardiovascular diseases: the Stanislas cohort.

In a given individual, the level of cardiovascular risk results from the combination of and interactions between genetic and environmental components. We choose to investigate segregation analysis of intermediate phenotypes in healthy nuclear families, belonging to the Stanislas cohort, a large familial cohort composed of 1006 families, which will be followed for 10 years. We developed a panel of 35 genetic markers including genes involved in lipid metabolism, regulation of blood pressure, thrombosis, platelet function, and endothelial cell adhesion. The allele frequencies of the studied polymorphisms were in agreement with those reported in other Caucasian populations. As an example of segregation analysis, we investigated carotid intima-media thickness (CIMT) variability in a subset sample of the Stanislas cohort. We found that about 30% of CIMT variability was attributable to genetic factors. Associations between CIMT and polymorphisms in apo CIII, cholesteryl ester transfer protein, methylene tetrahydrofolate reductase, and fibrinogen genes were observed and explained about 20% of CIMT variability in men. Furthermore, as another example of association studies, we investigated the relations between E-selectin polymorphisms and blood pressure interindividual variability and longitudinal changes in unrelated adults of this familial population. The E-selectin Phe554 allele was found associated with lower systolic blood pressure and diastolic blood pressure.

Adult↗

PubMed1999

A multilocus genotyping assay for candidate markers of cardiovascular disease risk.

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.

Adult↗

PubMed1999

Multilocus approach to cardiovascular risk.

Until now, our familial studies have showed that shared genetic and environmental factors are involved on lipid parameters variability. More precisely, being working on 119 families we have showed that: a) The apolipoprotein E (apo E) common polymorphism is involved in the total cholesterol, low density lipoprotein cholesterol (LDL-Chol), apo E, apo B levels variability, b) the apolipoprotein A-IV gene had no effect on lipid metabolism parameters variability, apo A-IV levels included, c) the apolipoprotein B gene was associated with total cholesterol, high density lipoprotein cholesterol, LDL-Chol, triglycerides and apo B levels genetic variability, d) the lipoproteine lipase (LPL) gene was responsible for 6.5% of the triglycerides variability, e) the apo E and LPL 447 polymorphisms influence in conjunction lipid parameters. These preliminary results on effects and combination effects of polymorphic genes show the interest of a multilocus approach. We have used in a subgroup of 416 individuals of a familial cohort (Stanislas Cohort) a prototype assay that genotypes a panel of 35 polymorphic sites on 15 candidate genes of Cardiovascular diseases. Each sample is amplified by two multiplex polymerase chain reactions, then hybridized to an array of immobilized, oligonucleotide probes. The frequencies of the rare alleles were in agreement with those reported by others in caucasian populations. The realisation of this multiplex assay in the 1,006 families of the Stanislas Cohort, which is underway, will allow us a better understanding of the inter-individual variability of lipids and will contribute to the determination of the genetic susceptibility of one's individual to cardiovascular risk.

Adult↗

PubMed1998

A multilocus genotyping assay for cardiovascular disease.

In our efforts to develop diagnostic tests for complex multifactorial disorders, and to assist the research community in evaluating genetic markers for predisposition to cardiovascular disease, we have developed a prototype assay to genotype up to 35 variable sites among 15 genes. The candidate markers in this panel were selected from biological pathways likely to contribute to the development and progression of cardiovascular disease. Each sample is amplified in two multiplex polymerase chain reactions that are then hybridized to an array of immobilized oligonucleotide probes. The assay has been applied to a population-based cohort representing 238 families; allele frequencies observed among 455 unrelated parents from this cohort agree with available literature values. Data from a cohort of 142 lipid-clinic patients were used to explore locus associations with arterial occlusion, as measured by quantitative angiography. This prototype assay provides a research tool for studies to assess the association of multiple markers with disease, and for clinical studies to evaluate marker association with patient responsiveness to experimental therapies.

Adult↗