Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: The aim of our study was to assess major cardiovascular event incidence, predictors, and mortality in ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective cohort study of all GPA or MPA, according to Chapel Hill Consensus Conference classification criteria, diagnosed between 1981 and 2015. Major cardiovascular event was defined as acute coronary artery disease, or ischemic stroke, or peripheral vascular disease requiring a revascularization procedure. We calculated the comparative morbidity/mortality figure (CMF) and we used Cox proportional hazards regression models to assess the risk of coronary artery disease, ischemic stroke associated with AAV, after adjusting for covariates. RESULTS: 125 patients, 99 GPA (79,2%) and 26 MPA (20,8%), were followed 88.4 ±â€¯78.3 months. Ischemic stroke incidence was four times higher than in the general population (CMF 4,65; 95% CI 4,06-5,31). Coronary artery disease incidence was four times higher than in the general population (CMF 4,22; 95% CI 1,52-11,68). Smoking habits and history of coronary artery disease were strongly associated with coronary artery disease occurrence (adjusted HR 8.8; 95% CI 2.12-36.56, and adjusted HR 10.3; 95% CI 1.02-104.5, respectively). ENT flare-up was an independent protective factor for coronary artery disease occurrence. We did not identify factors significantly associated with stroke occurrence. The age-adjusted mortality rate was 22.5 per 1000 person-years. Mortality in AAV was 1.5 times higher than in the general population (CMF 1.56; 95% CI 1.34-1.83). CONCLUSION: AAV have a significantly increased risk of mortality, ischemic stroke, and coronary artery disease.

Non-obstructive carotid atherosclerosis and patent foramen ovale in young adults with cryptogenic stroke.

BACKGROUND AND PURPOSE: Up to 50% of ischaemic strokes in young adults are classified as cryptogenic despite extensive work-up. We sought to evaluate the prevalence of non-obstructive carotid atherosclerosis (NOCA) and its association with patent foramen ovale (PFO) in young adults with cryptogenic stroke (CS). METHODS: Patients aged 18-54 years, consecutively treated for first-ever CS in an academic stroke service, were included. NOCA was assessed using carotid ultrasound examination and was defined as carotid plaque with <50% stenosis. PFO was diagnosed with transesophageal echocardiography. RESULTS: A total of 164 patients [mean age (SD) = 43.7 (8.5) years; 104 men] were included. A PFO was found in 79/164 (48.2%) patients. NOCA was demonstrated in 41/164 (25%) patients. NOCA was more common in patients without PFO [37.6% vs. 11.4%, P < 0.001; adjusted odds ratio (95% confidence interval), 0.24 (0.10-0.56)]. Older age (P = 0.046) and subcortical location of cerebral infarct (P = 0.015) were also associated with the absence of PFO, whereas hypertension, diabetes and smoking were not. CONCLUSIONS: This study demonstrates that NOCA is common in young adults with CS. NOCA is negatively associated with PFO. Detecting NOCA is an important component of stroke investigation in young adults.

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.

Evaluation of oral health related to body mass index.

OBJECTIVE: Poor oral health has previously been related to high body mass index (BMI). We aimed at exploring the link between BMI and several oral health markers, after adjustment for dietary patterns and plasma insulin, both of which could act as mediators. SUBJECTS AND METHODS: Dental examination was performed in a sample of 186 French subjects aged 35-64 years and selected from the general population to assess number of missing teeth, periodontitis, clinical attachment loss (CAL), probing pocket depth (PD), gingival index (GI) and plaque index (PI). Data collection also included a food-frequency questionnaire. BMI (considered as outcome variable) was categorized into quartiles, and as BMI<25; 25 ≤BMI<30; and BMI ≥ 30 kg m(-2) . RESULTS: After adjustment for age, gender, education level, smoking, physical activity, energy intake and C-reactive protein, BMI was statistically associated with missing teeth, PD and PI, but not with CAL, GI or periodontitis. After additional adjustment for 'high-carbohydrate' diet and plasma insulin or HOMA (homeostasis model assessment) index for insulin resistance, the statistical relationship between BMI and oral variables remained significant only for PD and PI. CONCLUSIONS: Plaque index, reflecting dental plaque, and PD, closely linked with periodontal inflammation and infection, are statistically associated with high BMI and obesity, independently of dietary patterns and insulin resistance.

Predicting CHD risk in France: a pooled analysis of the D.E.S.I.R., Three City, PRIME, and SU.VI.MAX studies.

BACKGROUND: We aimed to develop and validate a simple coronary heart disease (CHD) risk algorithm applicable to asymptomatic men and women in France, and to compare its accuracy with that of the last published version of the Framingham risk function for cardiovascular disease. DESIGN: A pooled analysis of four French prospective general-population studies. METHODS: The baseline and follow-up data from D.E.S.I.R., PRIME, Three City, and SU.VI.MAX studies were used. The 10-year CHD risk was estimated by the Cox proportional hazards model with candidate variables including age, gender, body mass index, waist circumference, family history of coronary heart disease, smoking status, diabetes status, systolic blood pressure, and total and high-density lipoprotein (HDL) cholesterol. RESULTS: The study population included 22,256 subjects (61.4% men) aged (SD) 56.0 years (8.3) without a personal history of CHD at baseline. After a mean follow-up of 8.0 years (2.3), 788 first CHD events occurred, 726 in men and 62 in women. The final model included age, gender, age × gender interaction, current smoking status, diabetes status, systolic blood pressure, total and HDL cholesterol. Using this model, the number of predicted coronary events fitted that given by the 10-year Kaplan-Meier survival estimates within each decile of estimated risk (calibration). This model had fair discrimination: Harrell C-index, 0.7831 (95% CI: 0.7704-0.7957). For comparison, the recalibrated Framingham risk function had equivalent performances compared to the French risk equation. CONCLUSION: Our 10-year French CHD risk equation based on traditional risk factors performed at least as well as the recalibrated Framingham cardiovascular disease risk function.

Higher mental stimulation at work is associated with improved cognitive functioning in both young and older workers.

The study examined whether mental stimulation received in the workplace positively affects cognitive functioning and rate of cognitive change. Data taken from the VISAT (ageing, health and work) longitudinal study concerned 3237 workers who were seen three times (in 1996, 2001 and 2006) and who were aged between 32 and 62 years at baseline. Measures of cognitive stimulation both at work and outside work were available at baseline. Cognitive efficiency was assessed on the three occasions through episodic verbal memory, attention and processing speed tests. Greater cognitive stimulation (at work and outside work) was associated with higher levels of cognitive functioning and a more favourable change over the 10-year follow-up. These results were obtained after adjustment for age, education, sex and a variety of medical, physical and psychosocial confounders. The study thus supports the hypothesis that exposure to jobs that are mentally demanding and that offer learning opportunities increases the level of cognitive functioning and possibly attenuates age-related decline. STATEMENT OF RELEVANCE: The effect of occupational activity on cognitive functioning is under-researched. This paper reports results from a substantive longitudinal study, with findings indicating that exposure to jobs that are mentally demanding are beneficial in increasing levels of cognitive functioning and possibly attenuating age-related decline.

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.

Lipoprotein (a) and risk of ischemic stroke in young adults.

UNLABELLED: Lipoprotein (a) [Lp(a)] is a LDL-particle linked to apoprotein (a) [apo(a)]. High Lp(a) plasma level is a risk factor for coronary heart disease and, in older men, for ischemic stroke. The role of Lp(a) as a risk factor for ischemic stroke in young adults is uncertain. METHODS: Lp(a) concentration was prospectively measured in 100 consecutive patients with acute ischemic stroke (58 men and 42 women) aged 18-55 years, and in 100 controls matched for age and gender. RESULTS: The distribution of Lp(a) concentration was skewed toward the highest and median tertiles in male patients. In multivariate logistic regression analyses adjusting on classical risk factors for ischemic stroke and lipid variables, Lp(a) concentration in the highest and medium tertiles compared with the lowest tertile was significantly associated with ischemic stroke in men (OR 3.55, 95% CI 1.33-9.48, p = 0.012), but was not in women (OR 0.42, 95% CI 0.14-1.26, p = 0.12). Although large vessel atherosclerosis was more common in men than in women, there were no differences in Lp(a) concentration according to the cause of ischemic stroke. CONCLUSION: Among subjects aged 18-55 years, a slightly elevated Lp(a) concentration was strongly and independently associated with ischemic stroke in men, but not in women. Further studies are required to elucidate the mechanisms underlying this gender-specific association.

Long-term treatment combining continuous subcutaneous insulin infusion with oral hypoglycaemic agents is effective in type 2 diabetes.

AIM: To compare over 3 years the efficacy of two treatment regimens combining continuous subcutaneous insulin infusion (CSII) and oral hypoglycaemic agents (OHA) in type 2 diabetic patients with HbA(1c) levels>8% despite OHA+/-insulin. METHODS: Fifty-nine patients were randomized to two groups. In both groups metformin was continued; CSII (velosulin) was used with minimal manipulation. Group A: the optimization of insulin doses was exerted on boluses to achieve postprandial glycaemia<9.99 mmol/l. Sulfonylurea, administered as a single dose at bedtime, was adjusted to attain fasting glycaemia<6.66 mmol/l. Group B: the optimization of insulin doses was exerted on night time basal rate to attain fasting glycaemia<6.66 mmol/l. Sulfonylurea, given before each meal, was adjusted to obtain postprandial glycaemia<9.99 mmol/l. RESULTS: During the 3 years follow-up, overall mean HbA(1c) values decreased similarly for both groups from baseline (9.45+/-0.83%) to 1, 2, 3 years (7.76+/-0.85%; 8.06+/-1.10%; 8.27+/-1.06% P<0.0001). The mean frequency of minor hypoglycaemia was 1.3+/-2.3 events per month per patient and 14 severe hypoglycaemic events occurred with no difference between the two groups. In both groups we observed a significant and similar weight gain and improvement in quality of life. CONCLUSION: Long-term combination therapy with OHA and CSII with only basic manipulation and optimization of insulin doses exerted on basal rate or on boluses is feasible, effective and well accepted in type 2 diabetes.

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.

Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis.

Activation of the Wnt/beta-catenin pathway has recently been shown to be crucial to the establishment of leukemic stem cells in chronic myeloid leukemia. We sought to determine whether beta-catenin was correlated to clonogenic capacity also in the acute myeloid leukemia (AML) setting. Eighty-two patients were retrospectively evaluated for beta-catenin expression by Western blot. beta-Catenin was expressed (although at various protein levels) in 61% of patients, and was undetectable in the remaining cases. In our cohort, beta-catenin expression was correlated with the clonogenic proliferation of AML-colony forming cells (AML-CFC or CFU-L) in methylcellulose in the presence of 5637-conditioned medium, and more strikingly with self-renewing of leukemic cells, as assessed in vitro by a re-plating assay. In survival analyses, beta-catenin appeared as a new independent prognostic factor predicting poor event-free survival and shortened overall survival (both with P<0.05). Furthermore, variations in beta-catenin protein levels were dependent on post-transcriptional mechanisms involving the Wnt/beta-catenin pathway only in leukemic cells. Indeed, beta-catenin negative leukemic cells were found to increase beta-catenin in response to Wnt3a agonist in contrast to normal counterparts. Altogether, our data pave the way to the evaluation of Wnt pathway inhibition as a new rationale for eradicating the clonogenic pool of AML cells.

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.

Lack of association between ADH3 polymorphism, alcohol intake, risk factors and carotid intima-media thickness.

OBJECTIVE: We assess the relationships between alcohol dehydrogenase 3 (ADH3) polymorphism, alcohol consumption and cardiovascular risk factor levels. METHODS: In a representative population sample from Southwestern France (614 men, 567 women, age 49.7+/-8.5 years), alcohol intake was assessed by questionnaire. RESULTS: Alcohol consumption was significantly related with higher levels of total and HDL cholesterol, triglycerides, apolipoprotein A-I in men and with higher levels of HDL cholesterol in women. Also, an inverse relationship between alcohol consumption and intima-media thickness was found in men. Conversely, in both genders, no differences were found between ADH3 genotypes regarding all cardiovascular risk factors studied and carotid intima-media thickness. Also, in both genders, no significant ADH3xalcohol interaction was found for all variables, and further adjustment on age, body mass index, educational level, smoking status or after excluding subjects on hypolipidemic or antihypertensive drug treatment did not change the results. CONCLUSION: We found no interaction between the ADH3 polymorphism and alcohol intake on cardiovascular risk factor levels and atherosclerotic markers in Southwestern France.

Metabolic syndrome is associated with markers of subclinical atherosclerosis in a French population-based sample.

Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). The relation of MetS with early stages of atherosclerosis, more important from a prevention perspective, has not been evaluated extensively. We examined the association of MetS, using WHO and NCEP definitions, with number of carotid and femoral plaques; carotid intima-media thickness (IMT); pulse wave velocity (PWV) in a random population-based sample of 1153 French adults (35-65 year). Impact of inflammatory factors (C-reactive protein and soluble intercellular adhesion molecule-1) on these parameters was also evaluated. Prevalence of MetS was 14.5 (CI: 12.3-16.0) and 17.5 (CI: 15.1-20.2)%, using NCEP and WHO definitions, respectively. MetS significantly predicted number of plaques, IMT, and PWV after adjustment for traditional risk factors (P<0.05). Inflammatory factors predicted peripheral plaques only. The risk of subclinical atherosclerosis was considerably increased with MetS (P<0.05); odds ratios ranged 1.80-2.15 with NCEP definition, and 1.48-1.97 with WHO definition. Individuals meeting both NCEP and WHO definitions had slightly greater risk of increased plaques, IMT, and PWV. MetS was strongly associated with subclinical atherosclerosis and aortic stiffness, and can be used as a surrogate marker for high CVD risk, deserving aggressive treatment.

[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.

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.

Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. Etude Cas-Témoin de l'Infarctus du Myocarde.

There is growing evidence that interleukin (IL) 6 plays an important role in the atherosclerotic process because of its role in mediating immune and inflammatory responses and inducing cell proliferation. The present study examined whether molecular variations at the IL-6 locus are involved in the predisposition to myocardial infarction. The entire coding region, 1,158 bp of the 5' flanking region and 237 bp of the 3' flanking region of the IL-6 gene were screened. We detected three nucleotide substitutions in the 5' region at positions -174 (G/C), -572 (G/C), and -596 (G/A) from the transcription start site, and one insertion/deletion in the 3' region at position +528 after the Stop codon. These polymorphisms were genotyped in the Etude Cas-Témoin de l'Infarctus du Myocarde study comparing male patients (n=640) and age-matched controls (n=719) from Northern Ireland and France. The IL-6/G-174C and IL-6/G-596A polymorphisms were in nearly complete association. Carriers of the IL-6/-174 C allele were more frequent in patients than in controls. The population-adjusted odds ratio for myocardial infarction associated with genotype CC+CG vs. GG was estimated as 1.34. In French patients the number of coronary arteries with greater than 50% stenosis was assessed by angiography. The IL-6/-174 C allele was more frequent in patients with two or fewer stenosed vessels than in patients with three-vessel lesions. These results suggest that genetic variation at the IL-6 locus is associated with susceptibility to myocardial infarction, especially events occurring on less extended lesions. These findings would be compatible with a lower IL-6 secretion associated with the IL-6/-174 C allele, itself or in combination with other promoter polymorphisms, leading to more unstable plaques.