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P Amouyel

Publications and source records attributed to P Amouyel.

At least 19 recordsLinked to original sources
PubMed2006

Homocysteine and coronary heart disease risk in the PRIME study.

INTRODUCTION: Despite recent meta-analyses suggesting that homocysteine is an independent predictor of coronary heart disease (CHD), there is debate regarding whether elevated homocysteine may be deleterious only in the presence of other risk factors, with which it acts synergistically to exert a multiplicative effect on CHD risk, emerging only as a CHD predictor in patients with pre-existing risk factors. The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study is a multicentre prospective study of 10593 men from France and Northern Ireland, investigating cardiovascular risk factors. We investigated: (1) whether higher homocysteine is associated with increased CHD risk in the PRIME case-control cohort; (2) whether homocysteine interacts synergistically with pre-existing CHD risk factors. METHODS: Homocysteine was measured in 323 participants who had developed CHD at 5-year follow-up and in 638 matched controls. RESULTS: There was no significant difference in homocysteine between cases and controls (p=0.18). Homocysteine was significantly higher in current smokers (geometric mean mumol/l (interquartile range mumol/l) 9.45 (7.43, 11.75)) compared with non-smokers (8.90 (7.32, 10.70); p=0.007). There was a significant interaction between homocysteine, smoking and CHD risk (chi2=10.29, d.f.=2, p=0.006). CONCLUSIONS: These findings suggest that elevated homocysteine is significantly associated with CHD risk in current smokers.

Biomarkers↗
PubMed2006

[Coronary mortality in France according to data sources].

BACKGROUND: Since 1985, two sources of information currently yield coronary disease frequency indicators among the French population: the national cause of death statistics set up by the CépiDC (INSERM), on the one hand, and three registries recording myocardial infarction and coronary deaths as defined by the WHO MONICA Project in three regions (Bas-Rhin, Communauté Urbaine de Lille, Haute-Garonne) on the other hand. Particularly, an inquiry for each possibly coronary death allows the registries to conclude positively (with or without a myocardial infarction), negatively or that no conclusion can be drawn because of insufficient data. The aim of the present work is to analyze concordance between coronary deaths issuing from the two sources according to their definition, while taking into account, or not, multiple causes listed on the death certificates. MATERIAL: and methods: In total, 4,664 deaths occurring in 2000 in the 35-64 year-old population of the three regions identified by the CépiDc were paired with the 812 deaths analyzed by the registries. The MONICA classification was compared with that of the CépiDC which used the ICD 10th Revision of the initial cause or after taking into account multiple causes. In each case, the concordance between the final classifications (coronary deaths or not) and the mortality ratio obtained from the two sources were computed. RESULTS: and conclusions: Eight hundred and six deaths could be paired: 310 with a coronary cause according to the registries, 420 of presumed coronary cause but with insufficient data and 76 of non coronary origin. Whereas the total number of coronary deaths was similar for the two sources, their concordance was relatively low (kappa=0.61). However, when the deaths with insufficient data were included in the MONICA definition, concordance decreased and a large underestimation (59%) of the coronary mortality is given by the national statistics as compared to the registries. Taking into account multiple causes of death and not only the initial cause permitted partly to reduce this underestimation (42%) and to increase concordance (kappa from 0.46 to 0.51). These findings have important consequences for international comparisons concerning coronary disease. Indeed, the MONICA Project showed that the frequency of deaths with insufficient data was especially elevated in France leading to an underestimation of the coronary death rates provided by the national statistics in comparison with other countries, particularly in Europe.

Adult↗
PubMed2005

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Adult↗
PubMed2005

APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study.

OBJECTIVE: To examine the association of plasma cholesterol levels, lipid-lowering agent (LLA) intake, and APOE genotype with dementia prevalence. METHODS: The Three-City Study is a population-based cohort of 9,294 subjects selected from the electoral rolls of three French cities (Bordeaux, Dijon, Montpellier). Baseline examination included extensive assessment of exposure to vascular risk factors (including cholesterol levels and LLA use [statin or fibrate]) and clinical diagnosis of dementia. RESULTS: Two percent of participants were demented at baseline. Overall 32.4% of participants had hyperlipidemia, and 15.6% were prescribed statins and 13.7% fibrates. After adjusting for age, gender, education level, and study center, the odds ratio (OR) for dementia was observed to be lower among LLA users (OR = 0.61, 95% CI = 0.41 to 0.91) compared with subjects taking no LLAs. There was no differential effect between statin and fibrate users. The odds for dementia were increased in subjects with hyperlipidemia (OR = 1.43, 95% CI = 1.03 to 1.99). Further adjustment for potential confounders did not modify these associations. In addition, the association between LLA intake and dementia was not modified by APOE genotype, whereas hyperlipidemia was significantly associated with increased dementia prevalence only in non-epsilon4 carriers and non-Alzheimer disease cases. Finally, in participants taking LLAs, the odds for dementia were decreased only in those having normal lipid levels. CONCLUSIONS: This observational study provides further evidence that lipid-lowering agents are associated with decreased risk of dementia, whereas hyperlipidemia is associated with increased odds for non-Alzheimer-disease-type dementia. These effects appear to be independent of all major potential confounders.

Aged↗
PubMed2005

Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME).

BACKGROUND: Data on the possible association between depressive disorders and inflammatory markers are scarce and inconsistent. We investigated whether subjects with depressive mood had higher levels of a wide range of inflammatory markers involved in coronary heart disease (CHD) incidence and examined the contribution of these inflammatory markers and depressive mood to CHD outcome. METHODS AND RESULTS: We built a nested case-referent study within the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study of healthy middle-aged men from Belfast and France. We considered the baseline plasma sample from 335 future cases (angina pectoris, nonfatal myocardial infarction, coronary death) and 670 matched controls (2 controls per case). Depressive mood characterized men whose baseline depression score (13-item modification of the Welsh depression subscale) was in the fourth quartile (mean score, 5.75; range, 4 to 12). On average, men with depressive mood had 46%, 16%, and 10% higher C-reactive protein, interleukin-6, and intercellular adhesion molecule-1 levels, respectively, independently of case-control status, social characteristics, and classic cardiovascular risk factors; no statistical difference was found for fibrinogen. The odds ratios of depressive mood for CHD were 1.35 (95% CI, 1.05 to 1.73) in univariate analysis and 1.50 (95% CI, 1.04 to 2.15) after adjustment for social characteristics and classic cardiovascular risk factors. The latter odds ratio remained unchanged when each inflammatory marker was added separately, and in this analysis, each inflammatory marker contributed significantly to CHD event risk. CONCLUSIONS: These data support an association of depressive mood with inflammatory markers and suggest that depressive mood is related to CHD even after adjustment for these inflammatory markers.

Biomarkers↗
PubMed2005

TAFI gene haplotypes, TAFI plasma levels and future risk of coronary heart disease: the PRIME Study.

OBJECTIVES: To evaluate the association of thrombin-activatable fibrinolysis inhibitor (TAFI) gene polymorphisms with the risk of coronary heart disease (CHD) and with TAFI levels measured by a newly developed enzyme-linked immunosorbent assay (ELISA) (TAFI-1B1), shown to be a reliable method for detecting quantitative variations in circulating TAFI. PATIENTS/METHODS: Six polymorphisms (C-2599G, G-438A, Ala147Thr, Thr325Ile, C + 1542G and T + 1583A) were genotyped and baseline plasma concentrations of TAFI were measured in a nested case-control design as part of the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study. Participants from France and Northern Ireland who had developed a CHD event during a 5-year follow-up (n = 321) were compared with 645 population- and age-matched control subjects. RESULTS: In France, the Thr147 allele was more frequent in cases than in controls (0.41 vs. 0.32; P = 0.02), whereas the reverse was observed in Northern Ireland (0.33 vs. 0.38; P = 0.19) (P = 0.01 for interaction). No other polymorphism was associated with CHD risk. Consistent with the results derived from the single-locus analysis, haplotype analysis revealed that the haplotype carrying the Thr147 allele was associated with increased risk of CHD in France while the reverse tended to hold in the Northern Ireland population. Single-locus and haplotype analyses revealed that two polymorphisms, C-2599G and Ala147Thr (or T + 1583A that is in nearly complete association with it), had additive effects on TAFI levels and explained >18% of TAFI variability. This effect was homogeneous in France and Northern Ireland, and in cases and controls who exhibited similar TAFI levels. CONCLUSIONS: Thrombin-activatable fibrinolysis inhibitor gene polymorphisms are strongly associated to plasma TAFI levels, but the relation to CHD risk is less clear.

Alleles↗
PubMed2005

Is there a relation between APOE expression and brain amyloid load in Alzheimer's disease?

BACKGROUND: It has been proposed that, independent of the epsilon4 allele, APOE promoter polymorphisms (-491 A/T and -219 G/T) may be risks factor for Alzheimer's disease by modulating APOE expression. OBJECTIVE: To measure the level of APOE expression in Alzheimer's disease. METHODS: Brains were obtained at necropsy from 114 patients with early and late onset sporadic Alzheimer's disease in Greater Manchester (UK) during years 1986 to 2001. Total RNA was extracted from 84 brains. Purified lymphocytes were obtained from fresh blood from 16 probable Alzheimer cases from Lille (France). APOE and beta-actin gene expression was determined by reverse transcriptase polymerase chain reaction in brain and lymphocytes. RESULTS: An inverse correlation between APOE expression level and A beta loads was observed. As previously described and extended to 114 cases here, an association between the -219 TT genotype and a higher level of parenchymal A beta deposition was found, irrespective of APOE epsilon4 allele status. This effect was more pronounced in older individuals, whereas higher A beta load appeared more closely related to epsilon4 in the younger age group (cut off point at the median age at death (72.5 years)). The -219 TT genotype was associated with a decrease in APOE expression. There was a 60% decrease in APOE expression in lymphocytes from probable Alzheimer cases v controls (p = 0.01). CONCLUSIONS: In the oldest individuals, reduced APOE expression, modulated in part by -219 G/T polymorphism, may influence risk and constitute a determinant A beta load in Alzheimer's disease.

Actins↗
PubMed2005

[Prevalence of dyslipidaemias in a representative sample of the French population].

Prevalence of dyslipidaemias in a representative sample of the French population Hypercholesterolaemia is a major factor of risk of coronary atherosclerosis. The prevalence of other types of dyslipidaemia in the general population remains poorly defined. This study was performed to measure the prevalence of various dyslipidaemias in the French population. A representative sample of 3508 men and women between the ages of 35 and 64 years was recruited by the "Multinational MONItoring of trends and determinants in CArdiovascular disease" centres of Lille, Strasbourg and Toulouse. We excluded 162 patients suffering from known cardiovascular disorders, and 409 individuals treated with lipid-lowering drugs. The prevalence of pure hypercholesterolaemia, defined as a total cholesterol concentration >6.2 mmol/l (2.4 g/l) and triglyceride concentration <2.3 mmol/l (2 g/l), was 30% (29-32%). The prevalence of HDL cholesterol concentration <1 mmol/l (0.4 g/l) in men, or <1.3 mmol/l (0.5 g/l) in women, was 12% (11-13%). The prevalence of mixed hyperlipidaemia, defined as a total cholesterol concentration >6.2 mmol/l (2.4 g/l) and triglyceride concentration >2.3 mmol/l (2 g/l) was 5% (4-6%). The prevalence of hypertriglyceridaemia, defined as a total cholesterol concentration <6.2 mmol/l (2.4 g/l) and triglyceride concentration >2.3 mmol/l (2 g/l) was 4% (3-5%). Low HDL cholesterol concentrations were associated with smoking, obesity, and absence of either regular physical exercise or alcohol consumption. This study confirmed the high prevalence of pure hypercholesterolaemia, and revealed an important prevalence of low HDL cholesterol concentration, which represents a major cardiovascular risk factor.

Adult↗
PubMed2005

[Treatment with statins in general medicine: dosage and effectiveness. Results of the observational study STATIMED].

Using a retrospective study in general medicine, we observed the rates of achieving targets for LDL-cholesterol as recommended by the French Agency for the Safety of Health care Products (AFSSAPS) in 2000, according to the types of statin prescribed and the dosages used. Out of 64 961 individuals treated with a statin between 31 July 2001 and 1 August 2002, we identified 22 065 patients treated with monotherapy, having had an LDL-cholesterol level performed at least 6 weeks after starting treatment or after changing statin or dosage, and no longer than 6 months before the start of our study in the other cases. In primary prevention, 81.9% of patients attained their objectives. The success rates became less impressive with increasing levels of cardiovascular risk: 95.6%, 86.9%, 72.0% and 56.3% for 0, 1, 2 and 3 or more risk factors respectively (p < 0.0001). For secondary prevention, the targets were only met for 62.8% of patients. In total, only 77.8% of the entire sample met their targets. For each type of statin, higher doses were used for patients with higher cardiovascular risk, but the percentage of patients reaching their LDL-cholesterol targets diminished. In conclusion, under the current conditions of managing lipid risk, the LDL-cholesterol targets are not sufficiently met. Extrapolating from the data obtained in this study, about 300 000 patients in France require better management than recommended in the 2000 AFSSAPS guidelines.

Aged↗
PubMed2004

Education, socioeconomic and lifestyle factors, and risk of coronary heart disease: the PRIME Study.

BACKGROUND: Socioeconomic differentials have been described in the risk of coronary heart disease (CHD) but the extent to which these differentials are explained by lifestyle factors has been examined to a lesser degree. We have examined the contribution of socio-economic factors to risk of CHD in a large cohort study in France and Northern Ireland. METHODS: In all, 10 593 men aged 50-59 years were examined between 1991 and 1994 in centres in Northern Ireland, Lille, Strasbourg, and Toulouse. Details were obtained for a number of socio-economic indicators from the men at the baseline examination. Men were also screened for evidence of CHD and followed annually by questionnaire for incident cases of coronary disease. Coronary events (coronary deaths, myocardial infarction, and angina) were documented by clinical records and were reviewed by an independent medical committee. RESULTS: In all, 842 men (8%) showed some evidence of CHD at screening examination and these men were more likely to be living in poorer material circumstances, be unemployed, or have had less full-time education than men without CHD at screening in both France and Northern Ireland. These relationships persisted following adjustment for all known risk factors for CHD. Among men who were initially free of CHD there were clear socio-economic differentials (years of full-time education, unemployment, and educational level) in the distribution of several risk factors for CHD, notably smoking habit (which differs in France and Northern Ireland), systolic blood pressure, body mass index, and fibrinogen. Total cholesterol in contrast showed no socio-economic differential whilst those with a shorter period of full-time education and the unemployed tended to be high consumers of alcohol. In this cohort of men free of CHD at baseline few socio-economic indicators showed relationships with risk of CHD by 5 years of follow-up. Only years in full education, educational level, and unemployment status when adjusted only for age and country showed significant relationships with CHD risk, but these became non-significant following adjustment for major CHD risk factors. CONCLUSIONS: Socio-economic differentials in long-term risk of CHD are apparent in both cohorts of men from France and Northern Ireland, particularly in men with evidence of CHD at baseline. Among men free of CHD at baseline, although there is strong evidence of socio-economic differentials in cardiovascular risk factors these do not contribute independently to risk of CHD at 5 years of follow-up in this large cohort of men from France and Northern Ireland.

Alcohol Drinking↗
PubMed2004

Assessment of Nurr1 nucleotide variations in familial Parkinson's disease.

Parkinson's disease (PD) is characterised by the death of dopaminergic neurons of the substantia nigra. As Nurr1 seems to regulate the development and maintenance of these neurons, we evaluated its potential role in Parkinson's disease using genetic methods. We genotyped two polymorphisms and screened a case-control sample for the presence/absence of two mutations recently described in exon 1. Our results failed to replicate the association initially observed and none of the mutations were present in our familial Parkinson's disease cases. These observations suggest that this gene is unlikely to play a major effect in French familial Parkinson disease.

Aged↗
PubMed2004

Endothelial cell markers and the risk of coronary heart disease: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study.

BACKGROUND: Tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), and thrombomodulin (TM) are 3 major hemostatic regulatory molecules synthesized by endothelium. Data from epidemiological studies aiming to evaluate the relation between plasma levels of these molecules and the development of coronary heart disease (CHD) are sparse or contradictory. METHODS AND RESULTS: We examined the association between these endothelial-cell markers and the incidence of fatal or nonfatal myocardial infarction (hard CHD) and stable or unstable angina (angina pectoris) in a prospective cohort (the PRIME Study) of nearly 10 000 healthy men recruited in France and Northern Ireland. We measured baseline plasma concentration of the free form of TFPI (f-TFPI), vWF, and the soluble form of TM (sTM) among 296 participants who subsequently developed CHD over the 5-year follow-up (158 with hard CHD and 142 with angina pectoris) and in 563 control subjects by use of a nested case-control design. Individuals with plasma vWF levels in the highest quartile showed a 3.04-fold increase in the risk of hard CHD compared with those in the lowest quartile (95% CI, 1.59 to 5.80). Individuals with f-TFPI levels below the 10th percentile had a 2.13-fold increased risk of hard CHD compared with those with levels above it (95% CI, 1.08 to 4.18). The risk for both molecules persisted after control for inflammatory parameters. Individuals with vWF levels in the highest quartile and f-TFPI levels below the 10th percentile presented a 6.9-fold increased risk of hard CHD compared with those with vWF levels in the lowest quartile and f-TFPI levels above the 10th percentile (95% CI, 1.3 to 37.8). CONCLUSIONS: vWF and f-TFPI plasma levels were independent risk factors for hard CHD events.

Angina Pectoris↗
PubMed2004

Overall alcohol intake, beer, wine, and systemic markers of inflammation in western Europe: results from three MONICA samples (Augsburg, Glasgow, Lille).

AIM: Anti-inflammatory effects of moderate alcohol consumption have been proposed to explain why moderate alcohol intake lowers coronary heart disease risk. We investigated the relationship between overall alcohol, beer or wine consumption and markers of systemic inflammation in three different geographical areas in Europe. METHODS AND RESULTS: Cross-sectional samples, each representative of the general population from Germany, Scotland, and France (MONICA Augsburg 1994/95, 2275 men and 2186 women, 25-74 years; Glasgow MONICA 1994/95, 561/616, 25-74 years, and MONICA Lille 1994/95, 581/574, 35-64 years) were studied. Alcohol intake was assessed by standardized interview. Adjusted means of C-reactive protein (CRP), fibrinogen, white blood cell (WBC) count, plasma viscosity (PV), and albumin were calculated among categories of alcohol intake, and separately for beer or wine consumption, by multiple linear regression. Self-reported moderate daily alcohol intake up to 40 g was associated with lower concentrations of CRP, fibrinogen, PV and WBC count, compared to non-drinking and heavy drinking, even after adjustment for various potential confounders. CONCLUSIONS: Moderate consumption of either wine or beer is associated with lower levels of systemic inflammatory markers in three different European areas, suggesting that ethanol itself might be largely responsible for the potential anti-inflammatory effects of these beverages.

Adult↗
PubMed2004

Change in cardiovascular risk factors in France, 1985-1997.

The change in the main cardiovascular risk factors in France was assessed using the MONICA population surveys conducted in the Urban Community of Lille, Bas-Rhin and Haute-Garonne. Trends in obesity, tobacco smoking, hypertension, hypercholesterolaemia and self-reported diabetes were established for the first (1985-1988) and the last (1995-1997) survey. The results indicate that the prevalence of overweight and obesity remained stable in both genders; tobacco smoking decreased in men but increased in women. Prevalence of hypertension decreased, and preventive measures improved in both genders. Prevalence of hypercholesterolaemia remained stable, and preventive measures improved only in men. Prevalence of self-reported diabetes increased solely in women, and preventive measures improved in both genders. However, in 1995-1997 still 40% of the treated hypertensive and 30% of the treated hypercholesterolaemic subjects were not adequately controlled. We conclude that prevalence and prevention of the main cardiovascular risk factors have evolved favourably in France, but the management of hypercholesterolaemia and hypertension can still be improved.

Adult↗
PubMed2004

Nutritional intakes of 1072 French free-living men with and without diagnosed cardiovascular risk factors.

OBJECTIVE: To compare the dietary intakes of free-living people with and without previously diagnosed diet-modifiable cardiovascular risk factors (hypertension, hypercholesterolaemia and diabetes). DESIGN: Cross-sectional survey on cardiovascular risk factors including a three-consecutive-day food record. SETTING: Multicentre setting in Lille (northern France), Strasbourg (north-east) and Toulouse (south-west) areas. SUBJECTS: A total of 1072 middle-aged men randomly selected from the general population: group 1 (504 men without previously diagnosed diet-modifiable risk factor), group 2 (377 men with one previously diagnosed diet-modifiable risk factor) and group 3 (191 men with two or three previously diagnosed diet-modifiable risk factors). INTERVENTIONS: None. RESULTS: Total daily energy intake equalled 10731 kJ/day (standard error: 119), 9991 (138) and 9737 (166) in groups 1, 2 and 3, respectively (P<0.0001 for ANOVA comparing the three groups), and daily energy intake without alcohol equalled 9860 (115), 9096 (132) and 8654 (159) kJ/day (P<0.0001). The proportion of calories from animal proteins (in daily energy intake without alcohol) increased from group 1 to 3 (P<0.0001), whereas the proportion from oligosaccharides decreased (P<0.0001). The proportion of calories from alcohol (in total daily energy intake) increased with the number of risk factors (P<0.0001). These results remained significant after adjustment for confounders. No significant group differences were found in the proportions of energy from polysaccharides, saturated, monounsaturated and polyunsaturated fats. CONCLUSIONS: As compared with subjects without risk factor, significant quantitative and qualitative changes are observed in individuals with diagnosed hypertension, hypercholesterolaemia or diabetes. However, lower consumptions of saturated fats and alcohol are needed.

Alcohol Drinking↗
PubMed2004

TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and the risk of coronary heart disease: The PRIME Study.

TLR4 and CD14 are two components of the LPS receptor complex, which are considered to play a key role in the pathogenesis of atherosclerosis. TLR4/Asp299Gly and CD14/C-260T polymorphisms are thought to modulate the activity of this complex. The aim of the study was to examine the association between the TLR4/Asp299Gly and CD14/C-260T polymorphisms, plasma levels of the soluble receptor CD14 (sCD14), and the incidence of coronary heart disease (CHD) in a prospective cohort (the PRIME Study) of 9758 healthy men aged 50-59 years recruited in France and Northern Ireland. A nested case-control design was used, comparing the 249 participants who developed a CHD event during the 5-year follow-up with 492 population- and age-matched control subjects. The two polymorphisms were genotyped and baseline plasma concentrations of sCD14 were measured. None of the two polymorphisms, or sCD14 levels, either considered alone or in combination, were associated with the risk of CHD. The CD14/C-260T allele was associated with increased plasma concentrations of soluble thrombomodulin and vascular cell adhesion molecule-1 and, to a lesser extent, sCD14. No relationship was observed between the TLR4 polymorphism and, any of the inflammatory and endothelial markers measured. The TLR4/Asp299Gly and CD14/C-260T polymorphisms and plasma sCD14 concentrations do not appear as significant predictors of the risk of CHD in healthy individuals.

Amino Acid Substitution↗
PubMed2004

Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease.

Cerebral accumulation of beta-amyloid peptide (A beta) is a central event in the pathogenesis of Alzheimer's disease (AD). Endothelin-converting enzyme-1 (ECE-1) is a candidate A beta-degrading enzyme in brain, but its involvement in AD pathogenesis was never assessed. We first performed brain immunocytochemistry, using a monoclonal anti-ECE-1 antibody, and observed neuronal ECE-1 expression in various cortical regions of nondemented subjects. In the hippocampus, ECE-1 immunoreactivity showed a stereotypical pattern inversely correlated with susceptibility to A beta deposition, further suggesting a physiological role in A beta clearance. In order to undertake a genetic association study, we identified a functional genetic variant (ECE1B C-338A) located in a regulatory region of the ECE1 gene. We showed that the A allele is associated with increased transcriptional activity in promoter-reporter gene assays and with increased ECE-1 mRNA expression in human neocortex. In a case-control study involving 401 patients with late-onset AD and 461 aged controls, we found that homozygous carriers of the A allele had a reduced risk of AD (OR=0.47, 95% CI 0.25-0.88). This finding was strengthened by the analysis of two other genetic variants of the ECE1 gene, which showed that the genetic association is extended over at least 13 kilobases of the gene sequence. Our results suggest that ECE-1 expression in brain may be critical for cortical A beta clearance and offer new potential targets for therapeutic interventions in AD.

Adult↗