A Role for Behavior in the Relationships Between Depression and Hostility and Cardiovascular Disease Incidence, Mortality, and All-Cause Mortality: the Prime Study.

BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits. PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality. METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support. RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p < 0.001). Following adjustment for behavioral factors, all relationships were attenuated both when accounting for and not accounting for other psychological variables. Associations with all-cause mortality remained significant (smallest SHR = 1.14, p = 0.04). Of the behaviors included, the most significant contribution to outcomes was found for smoking, but a role was also found for fruit and vegetable intakes and high alcohol consumption. CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships.

Alcohol consumption patterns and body weight.

BACKGROUND/AIMS: The impact of alcohol on health depends on both the total amount ingested per week and the drinking pattern. Our goal was to assess the relationship between drinking occasions and anthropometric indicators of adiposity. METHODS: For this cross-sectional study, 7,855 men aged 50-59 years were recruited between 1991 and 1993 in France. Clinical and anthropometric data were obtained in a standardized clinical examination by trained staff. Alcohol intake was assessed by a questionnaire recording daily consumption of each type of alcohol during a typical week. RESULTS: 75% of the participants drank alcohol daily (264.7 ml per week). For a given total alcohol intake and after adjustment of confounders, the number of drinking episodes was inversely correlated with body mass index (p < 0.0001) and waist circumference (p < 0.0001). The odds ratio (95% confidence interval) for obesity was 1.8 (1.3-2.4) for occasional (1-2 days/week) and 1.6 (1.2-2.1) for frequent drinkers (3-5 days/week) compared with daily drinkers. This correlation was less pronounced in moderate (<140 ml/week) than intermediate consumers (140-280 ml/week). In heavy consumers (>280 ml/week), the intake was almost always daily. The results were similar for wine and beer consumption. CONCLUSION: Our findings suggest that drinking occasion is a risk indicator of obesity independent of total alcohol intake.

Do lifestyle behaviours explain socioeconomic differences in all-cause mortality, and fatal and non-fatal cardiovascular events? Evidence from middle aged men in France and Northern Ireland in the PRIME Study.

OBJECTIVE: To examine the contribution of lifestyle behaviours to the socioeconomic gradient in all-cause mortality, and fatal and non-fatal cardiovascular events. METHOD: 10,600 men aged 50-59 years examined in 1991-1994 in Northern Ireland (NI) and France and followed annually for deaths and cardiovascular events for 10 years. Baseline smoking habit, physical activity, and fruit, vegetable, and alcohol consumption were assessed. RESULTS: All lifestyle behaviours showed marked socioeconomic gradients for most indicators in NI and France, with the exception of percentage of alcohol consumers in NI and frequency of alcohol consumption in NI and France. At 10 years, there were 544 deaths from any cause and 440 fatal and non-fatal cardiovascular events. After adjustment for country and age, socioeconomic gradients were further adjusted for lifestyle behaviours. For total mortality, the median residual contribution of lifestyle behaviours was 28% and for cardiovascular incidence, 41%. When cardiovascular risk factors were considered in conjunction with lifestyle behaviours these percentages increased to 38% and 67% respectively. CONCLUSION: Lifestyle behaviours contribute to the gradient in mortality and cardiovascular incidence between socioeconomic groups, particularly for cardiovascular incidence, but a substantial proportion of these differentials was not explained by lifestyle behaviours and cardiovascular risk factors.

Adipocytokines and the risk of coronary heart disease in healthy middle aged men: the PRIME Study.

BACKGROUND: Adipokines play an important role in glucose, lipid and lipoprotein metabolisms, as well as in coagulation and inflammatory processes. So far, studies have evaluated the association of individual adipokines with future coronary heart disease (CHD) event and provided mixed results. OBJECTIVES: We sought to investigate the association of a set of adipocytokines, including total adiponectin, adipsin, resistin, leptin and plasminogen activator inihibitor-1 (PAI-1), with future CHD events in apparently healthy men. METHODS: We built a nested case-control study within the PRIME Study, a multicenter prospective cohort of 9779 healthy European middle-aged men. Total adiponectin, adipsin, resistin, leptin and PAI-1 were measured in the baseline plasma sample of 617 men who developed a first CHD event (coronary death, myocardial infarction, stable or unstable angina) during 10 years of follow-up and in 1215 study-matched controls, by multiplex assays using commercial kits. HRs for CHD were estimated by conditional logistic regression analysis. RESULTS: Median concentrations of total adiponectin, adipsin and resistin were similar in cases and in controls, whereas those of leptin and PAI-1 were higher in cases than in controls, 6.30 vs 5.40 ng ml(-1), and 10.09 vs 8.48 IU ml(-1), respectively. The risk of future CHD event increased with increasing quintiles of baseline leptin and PAI-1 concentrations only in unadjusted analysis (P-value for trend <0.003 and <0.0001, respectively). However, these associations were no longer significant after adjustment for usual CHD risk factors including hypertension, diabetes, smoking, total cholesterol, triglycerides and HDL cholesterol. Conversely, baseline CRP and IL-6 levels remained associated with CHD risk in multivariate analysis. CONCLUSIONS: In apparently healthy men, circulating total adiponectin, adipsin, resistin, leptin and PAI-1 were not independent predictors of future CHD event.

Association of macronutrient intake patterns with being overweight in a population-based random sample of men in France.

AIM: Diet is considered an important modifiable factor in the overweight. The role of macronutrients in obesity has been examined in general in selected populations, but the results of these studies are mixed, depending on the potential confounders and adjustments for other macronutrients. For this reason, we examined the association between macronutrient intake patterns and being overweight in a population-based representative sample of middle-aged (55.1+/-6.1 years) men (n=966), using various adjustment modalities. METHODS: The study subjects kept 3-day food-intake records, and the standard cardiovascular risk factors were assessed. Weight, height and waist circumference (WC) were also measured. RESULTS: Carbohydrate intake was negatively associated and fat intake was positively associated with body mass index (BMI) and WC in regression models adjusted for energy intake and other factors, including age, smoking and physical activity. However, with mutual adjustments for other energy-yielding nutrients, the negative association of carbohydrate intake with WC remained significant, whereas the associations between fat intake and measures of obesity did not. Adjusted odds ratios (95% confidence interval) comparing the highest and lowest quartiles of carbohydrate intake were 0.50 (0.25-0.97) for obesity (BMI>29.9) and 0.41 (0.23-0.73) for abdominal obesity (WC>101.9 cm). CONCLUSION: Consistent negative associations between carbohydrate intake and BMI and WC were seen in this random representative sample of the general male population. The associations between fat intake and these measures of being overweight were attenuated on adjusting for carbohydrate intake. Thus, the balance of carbohydrate-to-fat intake is an important element in obesity in a general male population, and should be highlighted in dietary guidelines.

Successful overweight prevention in adolescents by increasing physical activity: a 4-year randomized controlled intervention.

BACKGROUND: Population-based studies directed at promoting physical activity in youth have shown limited success in obesity prevention. OBJECTIVE: To assess whether an intervention integrating environmental changes to induce sustained changes in physical activity, prevents overweight in adolescents. DESIGN: Four-year randomized trial started in 2002 in eight middle schools of Eastern France. The intervention, randomized at school level, was designed to promote physical activity by changing attitudes through debates and attractive activities, and by providing social support and environmental changes encouraging physical activity. SUBJECTS: Nine hundred and fifty four 12-year-old six-graders. MEASUREMENTS: Body mass index (BMI), body composition, physical activity by questionnaire, plasma lipids and glucose, insulin resistance. RESULTS: Intervention students had a lower increase in BMI (P=0.01) and age- and gender-adjusted BMI (P<0.02) over time than controls. The differences across groups of the age- and gender-adjusted BMI changes (95% confidence interval (CI)) were -0.29 (-0.51; -0.07) kg/m2 at 3 years, -0.25 (-0.51; 0.01) kg/m2 at 4 years. An interaction with baseline weight status was noted. The intervention had a significant effect throughout the study in initially non-overweight adolescents (-0.36 (-0.60;-0.11) kg/m2 for adjusted BMI at 4 years), corresponding to a lower increase in fat mass index (P<0.001). In initially overweight adolescents, the differences observed across groups at 2 years (-0.40 (-0.94; 0.13) kg/m2 for adjusted BMI) did not persist over time. At 4 years, 4.2% of the initially non-overweight adolescents were overweight in the intervention schools, 9.8% in the controls (odds ratio=0.41 (0.22; 0.75); P<0.01). Independent of initial weight status, compared with controls, intervention adolescents had an increase in supervised physical activity (P<0.0001), a decrease of TV/video viewing (P<0.01) and an increase of high-density cholesterol concentrations (P<0.0001). CONCLUSION: Enhancing physical activity with a multilevel program prevents excessive weight gain in non-overweight adolescents. Our study provides evidence that prevention of obesity in youth is feasible.

Adiponectin is associated with lipid profile and insulin sensitivity in French adolescents.

AIM: The favourable relationship of adiponectin with the metabolic profile demonstrated in adults has been less studied in youths. The aim of this study was to examine cross-sectional and longitudinal associations between adiponectin and various metabolic risk factors in 12-year-old adolescents. METHODS: Subjects were participants in a randomized controlled study to promote physical activity (PA). Cross-sectional associations were assessed at entry in 2002 among 647 PA-exposed and control first-level students (49% male, 11.6+/-0.6 years of age). Longitudinal analyses involved 288 control students surveyed in 2002 and 2004. Baseline measurements included fasting serum adiponectin and anthropometric indices (body mass, waist size, body fat [BF] by bioimpedance), insulin concentration, homeostasis model assessment (HOMA), high-density lipoprotein (HDL) cholesterol, triglycerides (TG), soluble TNF-alpha receptor 1 (sTNF-alpha R1) and high-sensitivity C-reactive protein. Analyses were performed with generalized linear mixed-effects models, taking into account correlations among adolescents in the same school. RESULTS: Cross-sectionally, plasma adiponectin was inversely associated with obesity indices, especially waist size (P<10(-2)), HOMA (P<0.03), insulin (P<0.04), TG (P<10(-2)) and sTNF-alpha R1 (P<0.05), and positively related to HDL cholesterol (P<10(-4)), after adjusting for age, gender, sexual maturity, sports participation and adiposity when relevant. Longitudinally, a higher baseline adiponectin level was associated with a more favourable two-year change in TG (P<0.05), even after accounting for baseline TG, and two-year BF and insulin changes. CONCLUSION: The findings of this study suggest a favourable relationship between adiponectin and both metabolic profile and subsequent changes in TG level in young adolescents.

Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction.

A polymorphism of the CETP gene (CETP/TaqIB) with two alleles B1 (60%) and B2 (40%) has been investigated in relation to lipid variables and the risk of myocardial infarction in a large case-control study (ECTIM) of men aged 25-64. No association was observed between the polymorphism and LDL or VLDL related lipid variables. Conversely, B2 carriers had reduced levels of plasma CETP (P < 0.0001) and increased levels of HDL cholesterol (P < 0.0001) and of other HDL related lipid variables. The effects of the polymorphism on plasma CETP and HDL cholesterol were independent, suggesting the presence of at least two functional variants linked to B2. A search for these variants on the coding sequence of the CETP gene failed to identify them. The effect of B2 on plasma HDL cholesterol was absent in subjects drinking < 25 grams/d of alcohol but increased commensurably, with higher values of alcohol consumption (interaction: P < 0.0001). A similar interaction was not observed for plasma CETP. The odds-ratio for myocardial infarction of B2 homozygotes decreased from 1.0 in nondrinkers to 0.34 in those drinking 75 grams/d or more. These results provide the first demonstration of a gene-environment interaction affecting HDL cholesterol levels and coronary heart disease risk.

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.

Depressed mood and dietary fish intake: direct relationship or indirect relationship as a result of diet and lifestyle?

Previous studies have suggested an association between depressed mood and the dietary intake of fish. In all cases, however, dietary fish intake has been considered at the exclusion of all other aspects of the diet. This analysis investigates associations between depressed mood and dietary fish intake, while also concurrently investigating intake of a number of other dietary components. The analysis is conducted on data from 10,602 men from Northern Ireland and France screened for inclusion into the PRIME cohort study. Depressed mood was assessed using a self-report questionnaire based on the Welsh Pure Depression sub-scale of the Minnesota Multiphasic Personality Inventory, diet was assessed using a Food Frequency Questionnaire, and limited demographics were also measured. Using regression, depressed mood is initially inversely associated with dietary fish intake. On inclusion of all other dietary variables, the strength of this relationship reduces but remains, and significant associations with a number of other foods are also found. On additional inclusion of all demographic variables, the strength of the above relationships again reduces, and associations with various measures of socio-economic status and education are also significant. These findings suggest that depressed mood is associated with fish intake both directly, and indirectly as part of a diet that is associated with depression and as part of a lifestyle that is associated with depression. Additional support for these conclusions is also provided in the pattern of associations between depressed mood and diet in the two countries. The relative contributions of fish intake to depressed mood both directly and indirectly are yet to be determined. However, while diet is not measured and until lifestyle can be adequately measured, the potential roles of diet and lifestyle in the association between depressed mood and dietary fish intake should not be ignored.

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.

Metabolic syndrome and coronary heart disease risk in a population-based study of middle-aged men from France and Northern Ireland. A nested case-control study from the PRIME cohort.

Metabolic Syndrome (MetS) was found associated with an increased CHD risk in several studies but data about this relationship in Southern Europe are lacking. We studied the association of MetS according to three different indexes (the National Cholesterol Education Program's definition (NCEP), a modified World Health Organization's definition (WHO) and the recent International Diabetes Federation's definition (IDF)) with CHD risk in a case-control study nested within the PRIME cohort, composed of subjects from France (Southern Europe) and Belfast (Northern Europe). The PRIME prospective study is composed of 10 592 men, aged 50-59 at baseline and followed for 5 years. Subjects included in this nested case-control study were 296 cases of incident CHD and 540 controls, who remained free of CHD during the 5 years of follow-up of the PRIME cohort and matched for age, recruitment centre and recruitment date. All subjects had questionnaires and a medical examination at baseline, and a blood sample was taken. Using the IDF's, the WHO's and the NCEP's definitions respectively, the frequency of MetS was 38.9%, 35.5% and 29.7% in cases and 32.4%, 28.7% and 22.6% in controls. After adjustment for physical activity, smoking and drinking habits, MetS was associated with CHD risk whichever the definition used (ORIDF=1.41 [1.02-1.95], P<0.04, ORWHO=1.40 [1.01-1.94], P<0.05 and ORNCEP=1.46[1.04-2.04], P<0.04). These results were homogeneous in France (low risk of CHD) and Belfast (high risk of CHD). Our results add further evidence that MetS is predictive of CHD risk in middle-aged men from Northern and Southern Europe, and highlight differences between the three definitions studied.

ICAPS: a multilevel program to improve physical activity in adolescents.

OBJECTIVES: ICAPS (Intervention Centred on Adolescents' Physical activity and Sedentary behaviour) is aimed at preventing excessive weight gain and cardiovascular risk in adolescents by promoting physical activity (PA) with an emphasis on recreational and daily-life PA, with a lifelong perspective. DESIGN: Randomized study designed to last for four years. Study cohort constituted of 954 first-level students (91% of eligible pupils), aged 11.7 +/- 0.6 y (mean +/- SD) from four pairs of schools randomly selected in eastern France, after sociogeographical stratification. In each pair, intervention status was randomised at school-level. The program, not limited to school settings, involves multiple partners with three objectives: 1) changing attitudes through debates and access to attractive activities during breaks and after-school hours, 2) encouraging social support, 3) providing environmental conditions that enable PA. Adapted times and places, open participation, emphasis on fun, meeting with others and absence of competitive aspects are used to reduce usual barriers to PA. Accessibility and safety are permanent concerns. RESULTS: Prevalence of overweight was 23.7%. High participation rates were attained (50% participated in at least one weekly activity). At six-month, the proportion of intervention adolescents not performing supervised PA out of academic PA was reduced by half (36% to 17% vs 42% to 42% in controls P < 10-4); the proportion of those spending > 3 h/day in sedentary occupations decreased (34% to 28% vs 27% to 36%; P < 10-4). CONCLUSION: These data demonstrate the feasibility of implementing a multilevel PA intervention program in adolescents. Six-month results document increased PA and decreased sedentary behaviour.

[Coronary mortality in France according to data sources]. / Mortalité coronaire en France selon les sources d'information.

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.

Food groups associated with a reduced risk of 15-year all-cause death.

BACKGROUND/OBJECTIVES: Long-term observational cohorts provide the opportunity to investigate the potential impact of dietary patterns on death. We aimed to investigate all-cause death according to the consumption of selected food groups, and then to identify those independently associated with reduced mortality. SUBJECTS/METHODS: Population survey of middle-aged men randomly selected in the period 1995-1997 from the general population of three French areas and followed over a median of 14.8 years. Dietary data were collected through a 3-day food record. Cox modeling was used to assess the risk of death according to selected foods groups after extensive adjustment for confounders, including a diet quality index. RESULTS: The study population comprised 960 men (mean age 55.5 ±6.2 years). After a median follow-up of 14.8 (interquartile range 14.3-15.2) years, 150 (15.6%) subjects had died. Food groups that remained independently predictive of a lower risk of death after extensive adjustment were an above-median consumption of milk (adjusted relative risk: 0.61, 95% confidence interval (CI): 0.43-0.86, P-value=0.005), fruits and vegetables (0.68, 0.46-0.98, P-value=0.041) and a moderate consumption of yogurts and cottage cheese (0.50, 95% CI: 0.31-0.81, P-value=0.005), other cheeses (0.62, 0.39-0.97, P-value=0.036) and bread (0.57, 0.37-0.89, P-value=0.014). Besides, there was a nonsignificant trend for a higher risk of death associated with highest sodium intakes. CONCLUSIONS: Consumption of food groups that largely match recommendations is associated with a reduced risk of all-cause death in men. A diet providing moderate amounts of diverse food groups appears associated with the highest life expectancy.

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.

Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis.

BACKGROUND: Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influences its expression, predisposing individuals carrying certain genetic variants to more severe atherosclerosis. METHODS AND RESULTS: Single-strand conformation polymorphism analysis was carried out to search the promoter region of the gene encoding gelatinase B for naturally occurring genetic variation. As a result, an unreported common polymorphism was detected, which arose from a cytosine (C) to thymidine (T) transition at position -1562 relative to the start of transcription. Transient transfection experiments and DNA-protein interaction assays indicated that the T allele had a higher promoter activity than the C allele, which appeared to be due to preferential binding of a putative transcription repressor protein to the C allelic promoter. A sample of 584 male patients with myocardial infarction and 645 age-matched male healthy control subjects were genotyped. The allele frequencies were not significantly different between the cases and control subjects. However, in 374 patients with available angiographic data, 26% of those carrying 1 or 2 copies of the T allele had >50% stenosis in 3 coronary arteries, whereas only 15% of C/C homozygotes had triple-vessel disease. CONCLUSIONS: These data suggest that this functional genetic variation influences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype.

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.

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.

Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction.

The matrix Gla protein (MGP) is an important inhibitor of vessel and cartilage calcification that is strongly expressed in human calcified, atherosclerotic plaques and could modulate plaque calcification and coronary heart disease risk. Using a genetic approach, we explored this possibility by identifying polymorphisms of the MGP gene and testing their possible association with myocardial infarction (MI) and plaque calcification. Eight polymorphisms were identified in the coding and 5'-flanking sequences of the MGP gene. All polymorphisms were investigated in 607 patients with MI and 667 control subjects recruited into the ECTIM Study (Etude Cas-Témoins de l'Infarctus du Myocarde) and in 717 healthy individuals with echographically assessed arterial calcification and atherosclerosis who were participating in the AXA Study. In the ECTIM Study, alleles and genotypes were distributed similarly in patients and controls in the whole study group; in only 1 subgroup of subjects defined as being at low risk for MI were the concordant A-7 and Ala 83 alleles more frequent in patients with MI than in controls (P<0.003). In the AXA Study among subjects with femoral atherosclerosis, the same alleles were more common in the presence than the absence of plaque calcification (P<0.025). The other MGP polymorphisms were not associated with any investigated clinical phenotype. Transient transfection experiments with allelic promoter-reporter gene constructs and DNA-protein interaction assays were carried out to assess possible in vitro functionality of the promoter variants detected at positions -814, -138, and -7 relative to the start of transcription. When compared with the -138 T allele, the minor -138 C: allele consistently conferred a reduced promoter activity of -20% (P<0.0001) in rat vascular smooth muscle cells and of -50% (P<0.004) in a human fibroblast cell line, whereas the other polymorphisms, including -7, displayed no evidence of in vitro functionality. We conclude that the A-7 or Ala 83 alleles of the MGP gene may confer an increased risk of plaque calcification and MI; however, the observed relationships are weak or limited to subgroups of patients and therefore need confirmation.