Ideal Cardiovascular Health and Incident Cardiovascular Disease: Heterogeneity Across Event Subtypes and Mediating Effect of Blood Biomarkers: The PRIME Study.

BACKGROUND: The aim of this study was to investigate whether the association between baseline cardiovascular health (CVH) and incident cardiovascular disease differs according to coronary heart disease (CHD) and stroke subtypes, and to assess the mediating effect of inflammatory and hemostatic blood biomarkers. METHODS AND RESULTS: The association of ideal CVH with outcomes was derived in 9312 middle-aged men from Northern Ireland and France (whole cohort) in multivariable Cox proportional hazards regression analysis. The mediating effect of baseline inflammatory and hemostatic blood biomarkers was evaluated in a case-control study nested within the cohort after 10 years of follow-up. After a median follow-up of 10 years, 614 first CHD events and 117 first stroke events were adjudicated. Compared with those with poor CVH, those with an ideal CVH profile at baseline had a 72% lower risk of CHD (hazard ratio=0.28; 95% confidence interval, 0.17; 0.46) and a 76% lower risk of stroke (hazard ratio =0.24; 95% confidence interval, 0.06; 0.98). The magnitude of the risk reductions was similar for incident angina and myocardial infarction, but was lower for ischemic stroke. In the controls, the mean concentrations of high-sensitivity C-reactive protein, IL-6, and fibrinogen decreased with higher CVH status. Furthermore, the association of behavioral CVH with incident CHD was partly mediated by high-sensitivity C-reactive protein (16.69%), IL-6 (8.52%), and fibrinogen (7.30%) CONCLUSIONS: Our study shows no clear heterogeneity in the association of baseline CVH with the main subtypes of cardiovascular disease. This supports a universal promotion of ideal CVH for all cardiovascular disease subtypes. Furthermore, our mediation analysis suggests that the lower risk of CHD associated with ideal CVH is partly mediated by lower inflammatory and hemostatic blood biomarkers.

Age- and sex-specific causal effects of adiposity on cardiovascular risk factors.

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

Shed syndecan-2 inhibits angiogenesis.

Angiogenesis is essential for the development of a normal vasculature, tissue repair and reproduction, and also has roles in the progression of diseases such as cancer and rheumatoid arthritis. The heparan sulphate proteoglycan syndecan-2 is expressed on mesenchymal cells in the vasculature and, like the other members of its family, can be shed from the cell surface resulting in the release of its extracellular core protein. The purpose of this study was to establish whether shed syndecan-2 affects angiogenesis. We demonstrate that shed syndecan-2 regulates angiogenesis by inhibiting endothelial cell migration in human and rodent models and, as a result, reduces tumour growth. Furthermore, our findings show that these effects are mediated by the protein tyrosine phosphatase receptor CD148 (also known as PTPRJ) and this interaction corresponds with a decrease in active ß1 integrin. Collectively, these data demonstrate an unexplored pathway for the regulation of new blood vessel formation and identify syndecan-2 as a therapeutic target in pathologies characterised by angiogenesis.

Hazardous alcohol consumption is associated with increased levels of B-type natriuretic peptide: evidence from two population-based studies.

Russia has very high mortality from cardiovascular disease (CVD), with evidence that heavy drinking may play a role. To throw further light on this association we have studied the association of alcohol with predictors of CVD risk including B-type natriuretic peptide (BNP). Levels of BNP increase primarily in response to abnormal cardiac chamber wall stretch which can occur both as a result of atherosclerosis as well as due to other types of damage to the myocardium. No previous population-based studies have investigated the association with alcohol. We analysed cross-sectional data on drinking behaviour in 993 men aged 25-60 years from the Izhevsk Family Study 2 (IFS2), conducted in the Russian city of Izhevsk in 2008-2009. Relative to non-drinkers, men who drank hazardously had an odds ratio (OR) of being in the top 20 % of the BNP distribution of 4.66 (95 % CI 2.13, 10.19) adjusted for age, obesity, waist-hip ratio, and smoking. Further adjustment for class of hypertension resulted in only slight attenuation of the effect, suggesting that this effect was not secondary to the influence of alcohol on blood pressure. In contrast hazardous drinking was associated with markedly raised ApoA1 and HDL cholesterol levels, but had little impact on levels of ApoB and LDL cholesterol. Similar but less pronounced associations were found in the Belfast (UK) component of the PRIME study conducted in 1991. These findings suggest that the association of heavy drinking with increased risk of cardiovascular disease may be partly due to alcohol-induced non-atherosclerotic damage to the myocardium.

Cytokine phenotype, genotype, and renal outcomes at cardiac surgery.

BACKGROUND: Cardiac surgery modulates pro- and anti-inflammatory cytokine balance involving plasma tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) together with urinary transforming growth factor beta-1 (TGFß1), interleukin-1 receptor antagonist (IL1ra) and tumour necrosis factor soluble receptor-2 (TNFsr2). Effects on post-operative renal function are unclear. We investigated if following cardiac surgery there is a relationship between cytokine (a) phenotype and renal outcome; (b) genotype and phenotype and (c) genotype and renal outcome. Since angiotensin-2 (AG2), modulates TGFß1 production, we determined whether angiotensin converting enzyme insertion/deletion (ACE I/D) genotype affects urinary TGFß1 phenotype as well as renal outcome. METHODS: In 408 elective cardiac surgery patients we measured pre- and 24 h post-operative urinary TGFß-1, IL1ra and TNFsr2 and pre- and 2 h post-operative plasma TNFα and IL-10. Post-operative responses were compared for each cytokine in patients grouped according to presence or absence of renal dysfunction defined as a drop from baseline eGFR of greater than 25% (as calculated by the method of modification of diet in renal disease (MDRD)) occurring (1) within the first 24 and (2) 48 postoperative hours (early renal dysfunction), (3) on the fifth postoperative day (late renal dysfunction) or (4) at any time throughout the 5 day postoperative period (early and late combined). Patient genotype was determined for TNF/G-308A, TGFß1-509 C/T, IL10/G-1082A and ACE I/D. RESULTS: Post-operative plasma IL-10 and urinary TGFß1 responses were significantly higher in patients who developed early renal dysfunction. IL1ra and TNFsr2 responses were significantly lower 24h post-operatively in patients who developed late renal dysfunction. Genotype did not alter cytokine phenotype or outcome. CONCLUSIONS/INFERENCES: Cytokine profiling may help predict early and late renal dysfunction. Genotypes studied did not alter phenotype or outcome.

All-cause mortality and periodontitis in 60-70-year-old men: a prospective cohort study.

OBJECTIVE: To investigate the association between periodontitis and mortality from all causes in a prospective study in a homogenous group of 60- to 70-year-old West European men. METHODOLOGY: A representative sample of 1400 dentate men, (mean age 63.8, SD 3.0 years), drawn from the population of Northern Ireland, had a comprehensive periodontal examination between 2001 and 2003. Men were divided into thirds on the basis of their mean periodontal attachment loss (PAL). The primary endpoint, death from any cause, was analysed using Kaplan-Meier survival plots and Cox's proportional hazards model. RESULTS: In total, 152 (10.9%) of the men died during a mean follow-up of 8.9 (SD 0.7) years; 37 (7.9%) men in the third with the lowest PAL (<1.8 mm) died compared with 73 (15.7%) in the third with the highest PAL (>2.6 mm). The unadjusted hazard ratio (HR) for death in the men with the highest level of PAL compared with those with the lowest PAL was 2.11 (95% CI 1.42-3.14), p < 0.0001. After adjustment for confounding variables (age, smoking, hypertension, BMI, diabetes, cholesterol, education, marital status and previous history of a cardiovascular event) the HR was 1.57 (1.04-2.36), p = 0.03. CONCLUSION: The European men in this prospective cohort study with the most severe loss of periodontal attachment were at an increased risk of death compared with those with the lowest loss of periodontal attachment.

Dietary patterns and smoking in Northern Irish men: a population at high risk of coronary heart disease.

This study evaluated dietary habits of Northern Irish men who are at high risk of cardiovascular disease, stratified as never-, ex-, moderate-, or heavy-smokers. Participants were male volunteers (30 - 49 years) from a single workforce in Belfast (n = 765). Dietary information was collected using a validated food frequency questionnaire. For 'a priori' diet scores, never- and ex-smokers had a significantly higher fruit and vegetable score, Mediterranean diet score, and alternative Mediterranean diet score than moderate or heavy-smokers (all p < 0.05). For 'a posteriori' patterns, scores for the healthy, sweet tooth, and traditional dietary patterns, derived from principal component analysis, differed significantly by smoking status, being lower among smokers for the healthy and sweet tooth patterns, and higher in ex-smokers for the traditional pattern (all p < 0.05). When the 'a posteriori' patterns were included in models predicting likelihood of being in a particular smoking category with the 'a priori' patterns, the results for the fruit and vegetable score lost significance (p = 0.13). Both 'a priori' and 'a posteriori' dietary patterns identified smokers, particularly heavy smokers, as exhibiting fewer healthy dietary habits than never- or ex-smokers, but 'a posteriori' dietary patterns appeared to be more strongly associated with smoking status.

C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the PRIME study.

OBJECTIVE: To examine prospectively the association of high-sensitivity C-reactive protein, interleukin 6, and fibrinogen with sudden death in asymptomatic European men. METHODS AND RESULTS: Among the 9771 men from the Etude PRospective de l'Infarctus du Myocarde (PRIME) Study, 664 had a first coronary heart disease over 10 years, including 50 sudden deaths, 34 nonsudden coronary deaths, and 580 nonfatal coronary heart disease events. For each outcome, 2 matched controls, who were free of coronary heart disease at the index date, were randomly selected from the initial cohort (nested case control study design). There was a 3-fold increased risk (95% CI, 1.20 to 7.81) of sudden death between the upper and the lower third of interleukin 6 after adjustment for baseline confounders in conditional logistic regression analysis. Neither high-sensitivity C-reactive protein (hazard ratio(third versus first tertile)=1.27; 95% CI, 0.51 to 3.17) nor fibrinogen (hazard ratio(third versus first tertile)=1.90; 95% CI, 0.76 to 4.75) was associated with sudden death. For comparison, there was a 6-fold increased risk of nonsudden coronary death from the highest compared with the lowest tertile of fibrinogen and a trend toward an association with higher C-reactive protein and higher interleukin 6. All 3 inflammatory biomarkers were moderately, but significantly, associated with nonfatal coronary heart disease. CONCLUSIONS: Interleukin 6, but not high-sensitivity C-reactive protein or fibrinogen, is an independent predictor of sudden death in asymptomatic European men.

Relative contribution of lipids and apolipoproteins to incident coronary heart disease and ischemic stroke: the PRIME Study.

AIM: To compare within the same cohort the association of a large panel of lipids with the risk of incident coronary heart disease (CHD) and ischemic stroke events in participants of the Prospective Epidemiological Study of Myocardial Infarction. METHODS: In this binational (Northern Ireland and France) prospective cohort, we considered 9,711 men aged 50-59 years free of CHD and stroke at baseline (1991-1993). The hazard ratios of each lipid marker for CHD and ischemic stroke events were estimated in separate Cox proportional hazard models adjusted for age, study center, systolic blood pressure, antihypertensive treatment, current smoking status, body mass index and diabetes. RESULTS: After 10 years of follow-up, 635 men had a first CHD and 98 a first ischemic stroke event. Total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) A1 and Apo B100, their ratios and lipoprotein (a) [Lp(a)] were all significantly predictive of future CHD. Associations with ischemic stroke followed the same trend as for CHD, but with lower strength, and none were statistically significant. However, none of the differences between the hazard ratios for CHD and for ischemic stroke were statistically significant. CONCLUSIONS: In healthy, middle-aged men, total-C, HDL-C, LDL-C, non-HDL-C, triglycerides, Apo A1 and Apo B100, their ratios and Lp(a) are, if anything, weak predictors of ischemic stroke events over a 10-year period.

Effect of supplementation with B vitamins and antioxidants on levels of asymmetric dimethylarginine (ADMA) and C-reactive protein (CRP): a double-blind, randomised, factorial design, placebo-controlled trial.

PURPOSE: Cardiovascular risk factors such as elevated levels of asymmetric dimethylarginine (ADMA)/C-reactive protein (CRP) and homocysteine are potentially related to essential micronutrients such as certain B vitamins and antioxidant vitamins. The aim of the present study was to investigate whether supplementation with moderate doses of B vitamins and/or antioxidants could alter either ADMA and/or CRP concentrations in middle-aged, apparently healthy men with mildly elevated homocysteine levels. METHODS: A randomised, double-blind, factorial design, intervention study was carried out on 132 men with mildly elevated homocysteine levels, allocated to four groups (a) B vitamins alone--1 mg folic acid, 7.2 mg pyridoxine, 0.02 mg cyanocobalamin daily, (b) antioxidants alone--150 mg ascorbic acid, 67 mg vitamin E, 9 mg ß-carotene daily, (c) B vitamins with antioxidant vitamins, or (d) placebo. A total of 101 men completed the study to 8 weeks. RESULTS: When the percentage of baseline ADMA and CRP was examined at 8 weeks, no statistically significant differences were observed between the four groups (p = 0.21 and p = 0.90, respectively). Similar non-significant results were observed when analysis was stratified based on baseline CRP levels (<1.0 mg/L, p = 0.10; ≥1.0 mg/L, p = 0.64) and smoking status (all p ≥ 0.05). CONCLUSIONS: Supplementation with moderate doses of B vitamins and/or antioxidants did not alter either ADMA or CRP concentrations in these middle-aged, apparently healthy men with mildly elevated homocysteine levels.

Antioxidants and periodontitis in 60-70-year-old men.

OBJECTIVE: The aim was to investigate the association between periodontal health and the serum levels of various antioxidants including carotenoids, retinol and vitamin E in a homogenous group of Western European men. MATERIALS AND METHODS: A representative sample of 1258 men aged 60-70 years, drawn from the population of Northern Ireland, was examined between 2001 and 2003. Each participant had six or more teeth, completed a questionnaire and underwent a clinical periodontal examination. Serum lipid-soluble antioxidant levels were measured by high-performance liquid chromatography with diode array detection. Multivariable analysis was carried out using logistic regression with adjustment for possible confounders. Models were constructed using two measures of periodontal status (low- and high-threshold periodontitis) as dependent variables and the fifths of each antioxidant as a predictor variable. RESULTS: The levels of alpha- and beta-carotene, beta-cryptoxanthin and zeaxanthin were highly significantly lower in the men with low-threshold periodontitis (p<0.001). These carotenoids were also significantly lower in high-threshold periodontitis. There were no significant differences in the levels of lutein, lycopene, alpha- and gamma-tocopherol or retinol in relation to periodontitis. In fully adjusted models, there was an inverse relationship between a number of carotenoids (alpha- and beta-carotene and beta-cryptoxanthin) and low-threshold periodontitis. beta-Carotene and beta-cryptoxanthin were the only antioxidants that were associated with an increased risk of high-threshold severe periodontitis. The adjusted odds ratio for high-threshold periodontitis in the lowest fifth relative to the highest fifth of beta-cryptoxanthin was 4.02 (p=0.003). CONCLUSION: It is concluded that low serum levels of a number of carotenoids, in particular beta-cryptoxanthin and beta-carotene, were associated with an increased prevalence of periodontitis in this homogenous group of 60-70-year-old Western European men.

Respective contribution of conventional risk factors and antihypertensive treatment to stable angina pectoris and acute coronary syndrome as the first presentation of coronary heart disease: the PRIME Study.

OBJECTIVE: To test whether conventional risk factors and antihypertensive treatment were more predictive of stable angina (SA) than acute coronary syndrome (ACS) as the first presentation of coronary heart disease (CHD). DESIGN: We used data from the PRIME Study (Prospective Epidemiological Study of Myocardial Infarction), a prospective cohort of 9758 asymptomatic middle-aged men recruited from WHO MONICA centers in Northern Ireland and France between 1991 and 1993. SA and ACS events were registered during 5 years of follow-up. METHODS: Hazard ratios (HRs) of each risk factor measured at baseline for SA and ACS events were assessed using separate Cox proportional hazard models. Difference between HRs was estimated by the bootstrap method. RESULTS: After 5 years of follow-up, there were 114 SA and 178 ACS as the first presentation of CHD. Diastolic blood pressure [adjusted HRs for 1 standard deviation increase = 1.34; 95% confidence interval (CI): 1.17-1.54 vs. 1.04; 95% CI: 0.87-1.25; P for comparison between HRs = 0.012], and possibly cigarette smoking over or equal to 20 pack-years (adjusted HR = 2.07; 95% CI: 1.43-2.99 vs. 1.29; 95% CI: 0.83-2.01; P for comparison between HRs = 0.062) were more predictive of ACS than SA, whereas this was the opposite for antihypertensive treatment (adjusted HR = 2.18; 95% CI: 1.39-3.41 for SA vs. 1.28; 95% CI: 0.85-1.93 for ACS, P for comparison between HRs = 0.049). CONCLUSION: The present data support that SA and ACS, as the first presentation of CHD, may not share exactly the same determinants.

Relative risks for stroke by age, sex, and population based on follow-up of 18 European populations in the MORGAM Project.

BACKGROUND AND PURPOSE: Within the framework of the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, the variations in impact of classical risk factors of stroke by population, sex, and age were analyzed. METHODS: Follow-up data were collected in 43 cohorts in 18 populations in 8 European countries surveyed for cardiovascular risk factors. In 93 695 persons aged 19 to 77 years and free of major cardiovascular disease at baseline, total observation years were 1 234 252 and the number of stroke events analyzed was 3142. Hazard ratios were calculated by Cox regression analyses. RESULTS: Each year of age increased the risk of stroke (fatal and nonfatal together) by 9% (95% CI, 9% to 10%) in men and by 10% (9% to 10%) in women. A 10-mm Hg increase in systolic blood pressure involved a similar increase in risk in men (28%; 24% to 32%) and women (25%; 20% to 29%). Smoking conferred a similar excess risk in women (104%; 78% to 133%) and in men (82%; 66% to 100%). The effect of increasing body mass index was very modest. Higher high-density lipoprotein cholesterol levels decreased the risk of stroke more in women (hazard ratio per mmol/L 0.58; 0.49 to 0.68) than in men (0.80; 0.69 to 0.92). The impact of the individual risk factors differed somewhat between countries/regions with high blood pressure being particularly important in central Europe (Poland and Lithuania). CONCLUSIONS: Age, sex, and region-specific estimates of relative risks for stroke conferred by classical risk factors in various regions of Europe are provided. From a public health perspective, an important lesson is that smoking confers a high risk for stroke across Europe.

Contribution of cardiovascular risk factors to coronary risk in patients with intermittent claudication in the PRIME Cohort Study of European men.

BACKGROUND: Intermittent claudication (IC) is associated with an increased cardiovascular morbidity. The goal of the present study was to assess the contribution of conventional cardiovascular risk factors (CVRFs) to this increased risk. METHOD: The PRIME Study is a multicenter Prospective Cohort Study of 10 602 men recruited in 1991-1993, aged 50-59 at baseline and followed over 10 years. At baseline, a questionnaire on socio demographic data was self-administered and CVRFs were measured. Composite outcome consisted of incident MI, effort angina, unstable angina and coronary death. The standardized questionnaire of the London School of hygiene was used to identify claudicants. Data were analyzed using multivariate Cox models. RESULTS: Probable and possible cases of IC were reported by 1.4% (135) and 4.6% (442) of subjects, respectively. Compared to subjects with no claudication, the probable cases demonstrated higher rates of CVRFs. The incidence of CAD events was 7.23/1000 person-year. Compared to non claudicants, probable claudicants had an increased age and country adjusted risk of coronary events (HR (95% CI), 2.4 (1.5-3.7), p<0.0001). After further adjustments for school duration, family history of early myocardial infarction, tobacco consumption, alcohol consumption, BMI, systolic blood pressure, antihypertensive treatment, diabetes, total cholesterol, HDL-cholesterol, triglycerides and lipid-lowering treatment, participants with probable claudication had an increased risk of coronary events but this was no longer significant (HR (95% CI), 1.3 (0.8-2.1), p=0.23). CONCLUSION: IC is associated with an increased risk of developing coronary events. This association is largely explained by the coexistence of CVRFs.

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project.

BACKGROUND: Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the IL18 gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, IL18R1 and IL18RAP, with the risk of developing CVD. METHODS: Eleven tagging SNPs, 5 in IL18R1 and 6 in IL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD. RESULTS: We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 IL18 SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful. CONCLUSION: Our analysis suggests that the variability of IL18R1 and IL18RAP genes are unlikely to contribute to modulate the risk of CVD.

Osteopontin gene variation and cardio/cerebrovascular disease phenotypes.

We aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case-control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GENIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels (P=0.044 [ECTIM] P=0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20-0.74], P=0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques (P=0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants.

Smoking habits, waist circumference and coronary artery disease risk relationship: the PRIME study.

INTRODUCTION: Abdominal obesity is an important risk factor for coronary artery disease (CAD). The extent to which tobacco exposure influences the effect of abdominal adiposity on CAD incidence remains uncertain. Therefore, the goal of this study was to assess the effects of tobacco exposure on CAD risk associated with abdominal obesity. METHODS: A cohort of 9763 men, aged 50-59 years, without known CAD was followed 10 years for CAD events. Risk factors were recorded using a questionnaire, a clinical examination, including waist circumference (WC) and waist-to-hip ratio (WHR) and biological measurements. Cox regression was used for statistical analyses. RESULTS: During follow-up, there were 659 incident CAD events. BMI, WC, WHR, blood pressure, cholesterol, high-density lipid cholesterol and triglycerides, physical activity and alcohol intake varied across smoking exposure categories. The incidence of CAD increased across tertiles of waist circumference in never (5.1, 6.1 and 7.2 CAD events/1000 in first, second and third tertiles of WC distribution, respectively), former (6.6, 7.8 and 9.3 events/1000, across tertiles) and current smokers (9.4, 11 and 13.1 events/1000, across tertiles). After adjusting for age, centre, educational level, alcohol intake and physical activity, the relative risk of CAD was 1.28 (1.08-1.51) for 1 standard deviation increase of WC in never smokers, 1.23 (1.08-1.38) in former smokers and 1.14 (1.00-1.29) in current smokers. Similar results were observed for WHR. No evidence for heterogeneity among tobacco exposure strata for both WC and WHR was observed. CONCLUSION: In conclusion, the relative risk of CAD associated with abdominal obesity is homogeneous in never, former and current smokers. Therefore, smokers with abdominal obesity are at high absolute risk of CAD.

Persistently raised C-reactive protein levels are associated with advanced periodontal disease.

OBJECTIVE: The aim was to investigate whether there was an association between periodontitis or tooth loss in a homogeneous group of 60-70-year-old Western European men and either a sustained high or low level of C-reactive protein (CRP). MATERIAL AND METHODS: Men enrolled in a cohort study of cardiovascular disease in Northern Ireland were screened in 1990-1994 and rescreened in 2001-2004, when a periodontal examination was completed. High-sensitivity CRP was measured from fasting blood samples. There were 806 men with six or more teeth who had either a high level (>3 mg/l) or a lower level of CRP at both time points. Multivariate analysis was carried out using logistic regression with adjustment for possible confounders. Models were constructed with the CRP level as the outcome variable and various measures of periodontal status (low and high threshold periodontitis) or tooth loss as predictor variables. Confounders included in the analysis were known cardiovascular risk factors of age, smoking, diabetes, BMI and socioeconomic status. RESULTS: There were 67 men who had a high value of CRP (>3 mg/l) and 739 men who had a CRP value

Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: the MORGAM Project.

Interleukin-18 (IL-18) is a key inflammatory molecule suspected of being involved in the etiology of cardiovascular diseases (CVD). Five single nucleotide polymorphisms (SNPs) capturing the common genetic variation of the IL-18 gene (tag SNPs) were genotyped in five European prospective CVD cohorts including 1933 cases and 1938 non-cases as part of the MORGAM Project. Not a single SNP was found associated with CVD. However, a significant (P=0.002) gene-smoking interaction was observed. In smokers, the -105T allele was more frequent in cases than in non-cases (0.29 vs 0.25) and associated with an increased risk of disease (odds ratio (OR)=1.25 (1.07-1.45), P=0.005), whereas the inverse relationship tended to be observed in non-smokers (OR=0.90 (0.78-1.02), P=0.131). The gene-smoking interaction was broadly homogenous across the cohorts and was also observed through haplotype analyses. In conclusion, using the concerted effort of several European prospective CVD cohorts, we are able to show that one IL-18 tag SNP interacts with smoking to modulate the risk of developing CVD.