Which, and how limited number of polymorphisms should be selected per disease, risk assessment, health profile or biological system?
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Biomarkers↗
Biomedical subjects
C Sass
Publications and source records attributed to C Sass.
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↗
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↗
Serum myeloperoxidase concentration in a healthy population: biological variations, familial resemblance and new genetic polymorphisms.
Myeloperoxidase (MPO) has been involved in the pathogenesis of several diseases through excessive production of reactive oxygen species (ROS) as well as through its genetic polymorphism. The aims of this study were to identify the factors affecting MPO serum concentration, to study the familial resemblance of MPO levels and to investigate the association between newly described MPO polymorphisms as well as the G-463A one and MPO levels in a healthy population. MPO serum concentrations were measured by an enzymatic immuno-assay (EIA) in 82 healthy families of the STANISLAS Cohort and MPO genotype, determination was performed using PCR-restriction fragment length polymorphism or allele specific oligonucleotide assay. MPO concentrations were significantly higher in parents than in offspring. The factors affecting MPO levels were age, the number of white cells, smoking in fathers and oral contraceptive intake in mothers. They explain from 12.4% up to 35.9% of MPO variability in men and women, respectively. Family correlations of MPO concentrations were of similar magnitude. The -129A allele of a newly described G-129A substitution was significantly associated with decreased MPO levels, whereas the -463A allele was suggested to be associated with increased levels of lipid variables. In this study, we identified factors affecting MPO serum concentrations and showed that molecular variations of the gene have only a weak influence on MPO variability. In contrast, the association between the G-463A polymorphism and lipid levels would suggest a possible implication of MPO in the risk of cardiovascular diseases. These results have to be confirmed and further investigations will be conducted in that way.
Adolescent↗
Environmental and genetic determinants of intima-media thickness of the carotid artery.
1. The aim of the present study was to investigate carotid intima-media thickness (CIMT) in relation to anthropometric, environmental and genetic factors, as well as cholesterol and blood pressure levels. 2. The study sample was composed of 89 families, with no documented cardiovascular disease, consisting of 369 subjects (aged from 10 to 54 years) from the Stanislas cohort. 3. Carotid intima-media thickness was measured by B-mode ultrasonography. Fifteen genetic markers, including genes involved in lipid metabolism, the regulation of blood pressure, thrombosis, platelet function and endothelial cell adhesion, were studied by multiplex assay. 4. The effects of gender, age, smoking, alcohol, body mass index, cholesterol, blood pressure and genetic factors were studied using ANOVA and bivariate and regression analyses. 5. Segregation analysis was also performed to estimate the contribution of genetic and environmental factors to CIMT variability. 6. Carotid intima-media thickness values were not affected by age or by gender up to 18 years of age. Thereafter, CIMT values increased sharply in men and remained significantly higher than in women. 7. Approximately 30% of CIMT variability was attributable to genetic factors. Associations between CIMT and polymorphisms in the apolipoprotein CIII, cholesteryl ester transfer protein, methylene tetrahydrofolate reductase and fibrinogen genes were observed and explained approximately 20% of CIMT variation in men. 8. In women, none of the studied polymorphisms was associated with CIMT variation. 9. Our study gives new perspectives for understanding CIMT variability in healthy middle-aged subjects.
Adolescent↗
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↗
[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↗
[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↗
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↗
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↗
Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project.
As part of the ApoEurope Project, the apolipoprotein E (apo E) serum concentration and polymorphism were determined in 6934 healthy subjects aged 25-64 years recruited in six European countries: Finland; France; Greece; Northern Ireland; Portugal and Spain. Age and sex influenced apo E concentration with concentrations being significantly higher in men than in women for those aged between 25 and 44 years. The age effect differed between the sexes after the age of 44 years, displaying a linear increase in women and a plateau in men. As expected, the serum apo E concentration was highest in varepsilon2 carriers and lowest in varepsilon4 carriers in each country with a significantly higher frequency of the varepsilon4 allele in the northern regions. The main finding of this study was a clear increasing North-South gradient in serum apo E concentration independent of age, sex and apo E genotype. In subjects aged <45 years and with the varepsilon3/varepsilon3 genotype, apo E concentration was higher in the South-East (Greece) as compared to the North by 20% for men and 32% for women. In addition to the genetic polymorphism, the geographical area is an important factor to take into account when studying serum apo E concentration in multicentre studies and defining reference values.
Adult↗
Comparison of biological effects of DNA damage induced by ionizing radiation and hydrogen peroxide in CHO cells.
PURPOSE: Free OH radicals are considered to be the common mediator of DNA damage after ionizing radiation and oxidative stress. In particular, double-strand breaks (dsb) have a major impact on cell killing after irradiation, while the mechanism of cell killing is less clear for oxidative injury. The latter not only affects DNA, but also equally other cell compartments, such as membranes and mitochondria, which may trigger cell death. This study intended to clarify the relationship between DNA damage induction, repair and cell inactivation for hydrogen peroxide and ionizing radiation. MATERIALS AND METHODS: Chinese hamster ovary (CHO) cells were treated with H2O2 in serum-free medium in combination with/ without X-irradiation. DNA damage was measured using the alkaline unwinding method or neutral constant-field gel electrophoresis. Cell survival was recorded using the colony-formation assay. RESULTS: Hydrogen peroxide induced a large number of single-strand breaks (ssb>36000/cell) without impairing cell survival. This number reached a maximum (36 Gy-equiv. at 3 x 10(-4) mol/dm3) without further increase after higher concentrations. Repair kinetics of ssb were similar to those after irradiation. Dsb were found only after very high concentrations of H2O2 (>3 x 10(-2) mol/dm3), which is different from irradiation which generated ssb and dsb in the same dose range. A linear-quadratic increase of dsb was found with increasing concentrations of H2O2 suggesting a single or a pairwise action of OH radicals to form a dsb. After either irradiation or peroxide treatment cell killing was observed only after doses which also allowed dsb detection. The number of dsb calculated per lethal event was in the same range but slightly higher after irradiation (1.7-fold) than after H2O2 treatment. CONCLUSIONS: Cell killing after irradiation or hydrogen peroxide appears to be due to dsb, whereas cells withstand large numbers of single-strand lesions and other types of non-DNA damage occurring at lower concentrations of hydrogen peroxide. The number of ssb saturates at intermediate concentrations of H2O2 suggesting that a limited amount of chromatin-bound metal ions is available for OH radical generation.
Animals↗
Lipoprotein lipase (C/G)447 polymorphism and blood pressure in the Stanislas Cohort.
OBJECTIVE: Association between blood pressure and triglyceride levels, and between lipoprotein lipase (LPL) (C/G)447 polymorphism and triglyceride levels has been described. We investigated whether the LPL (C/G)447 polymorphism was associated with blood pressure (BP) levels and longitudinal changes. DESIGN AND PARTICIPANTS: For cross-sectional analysis, 767 men and 816 women (29-55 years) were selected from the Stanislas Cohort, a cohort of volunteers for a free health check-up. Only subjects without anti-hypertensive or lipid-lowering medication were included in the study. A subset of this sample population, 359 men and 337 women, had been followed during the 11 years prior to recruitment in the Stanislas Cohort and was used for longitudinal analysis. RESULTS: The cross-sectional study showed that serum triglyceride levels differed significantly according to LPL genotypes in both genders, the G447 allele being associated with the lowest triglyceride levels (P < or = 0.01). Univariate and multivariate analysis found that LPL polymorphism was not related to BP levels in men. In contrast, women with the LPL-G447 allele had lower systolic (SBP) and pulse (PP) pressure levels than those with the LPL-CC genotype (P < or = 0.01 and P < or = 0.05, respectively); this association being independent of triglyceride level. The longitudinal study showed LPL genotype was an independent predictor of PP and SBP follow-up levels in women; changes over 11 years being lower for LPL-G447 allele carriers (P < or = 0.05). These associations were independent of triglyceride level. CONCLUSION: The LPL-G447 allele was found associated with lower PP and SBP independently of triglyceride level in women. This result suggests that the LPL gene may influence blood pressure.
Adult↗
Associations of apolipoprotein E concentration and polymorphism with lipids and apolipoprotein levels in Chinese from Beijing and Shanghai.
The association of apolipoprotein E concentration and common polymorphism (codons 112/158) with lipid and apolipoprotein concentrations was studied in two Chinese healthy population samples from Beijing (n=99) and Shanghai (n=67). Body mass index and apolipoproteins E and AI and triglyceride concentrations were significantly different between the two populations (0.001<p<0.05), but apolipoprotein E common allele frequencies were not significantly different. Apolipoprotein E concentration was independently associated with apolipoproteins B and AI, total cholesterol and triglyceride concentrations in the Beijing group, but only with total cholesterol and apolipoprotein AI concentrations in the Shanghai group. Apolipoprotein E polymorphism was significantly associated with apolipoproteins E and AI, and triglyceride concentrations in the Beijing subjects (0.001<p<0.01), whereas apolipoprotein E polymorphism was significantly related only to apolipoprotein E concentration in the Shanghai group (p<0.001). This preliminary study with a limited number of subjects shows that the relations between both apolipoprotein E genotypes and concentration with lipid traits are not the same in the two studied Chinese populations.
Adolescent↗
Apolipoprotein E polymorphism and serum concentration in Alzheimer's disease in nine European centres: the ApoEurope study. ApoEurope group.
As part of the ApoEurope Project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the epsilon4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p<0.001). In addition, serum total cholesterol and triglyceride concentrations were lower in Alzheimer's disease (p<0.001), while that of apo Al was not affected. The decrease in serum apo E concentration was not accounted for by the epsilon4 allele, age or gender, suggesting that apo E concentration might represent an additional risk factor for Alzheimer's disease, complementary and independent of the epsilon4 allele. Further analysis will be aimed at determining whether the quantitative link between apo E concentration and Alzheimer's disease occurs through the effect of apo E genotype on lipid parameters or by other mechanisms.
Age Factors↗
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↗
Apolipoprotein E polymorphisms and concentration in chronic diseases and drug responses.
Apolipoprotein (apo) E is an important circulating and tissue protein involved in cholesterol homeostasis and many other functions. The common polymorphism in the coding region of the gene, four polymorphisms in the promoter region, other additional single nucleotide polymorphisms, as well as several apo E variants have been identified. The common coding polymorphism strongly influences the lipid metabolism and the circulating concentration of apo E itself. This polymorphism is at the origin of the implication of apo E in cardiovascular and neurodegenerative diseases, but also of the relation of apo E with longevity. Probably due to its many metabolic and functional consequences, apo E polymorphism has been shown to influence the responses of patients to several drugs (fibrates, statins, hormone replacement therapy, anti-Alzheimer drugs) or environmental interventions (black tea, alcohol, diet). Apo E genotyping may be clinically helpful in defining the risk of patients and their responses to therapeutics. Finally, circulating apo E concentration appears to be altered in diseases and can be modulated by some of the drugs cited above. This parameter can thus also give interesting clinical information and could be a therapeutic target, providing it is validated. At the present time, we cannot exclude that apo E concentration may be the most prominent apo E parameter to be considered in health and disease, while apo E polymorphisms would represent only secondary parameters influencing apo E concentration.
Alleles↗
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↗