Troponin and BNP are markers for subsequent non-ischaemic congestive heart failure: the Caerphilly Prospective Study (CaPS).

Objective: To examine the long-term predictive value of 28 biomarkers for subsequent non-ischaemic congestive heart failure (CHF) and separately for other cardiovascular outcomes (myocardial infarction (MI) and stroke). Methods: The Caerphilly Prospective Study recruited 2171 men aged 55-69 years from the general population in 1989-1993; men were screened for evidence of cardiovascular disease (CVD) and followed for clinical cardiovascular events. Fasting blood samples were stored at -70°C until assayed for novel biomarkers in 2010-2013. A competing risks proportional hazards regression analysis was used to estimate subhazard ratios (SHRs) for each biomarker for each cardiovascular outcome. Results: During follow-up (average 13 years), only new, initial events were evaluated in the whole cohort: 584 MIs, 313 strokes and 261 episodes of CHF (not associated with acute MI). In a subcohort of men who had no clinical history or evidence of CVD at baseline examination (n=1279) those in the top third of the distributions of troponin and B-type natriuretic peptide (BNP) showed a threefold increase in risk for subsequent CHF as a first event after adjustment for all conventional risk factors (SHRs 3.37, 95% CI 1.39 to 8.14 and 3.23, 95% CI 1.45 to 7.23), respectively, in contrast to moderate elevations in risk for acute MI (troponin SHR 1.63, 95% CI 1.10 to 2.41) and for stroke (BNP SHR 1.75 95% CI 1.06 to 2.88). Conclusion: Troponin and BNP could be considered as potentially useful screening tools to detect subjects without prior CVD at increased risk of developing CHF in subsequent years in addition to having lesser roles for predicting subsequent MI (troponin) or stroke (BNP).

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.

Is dieting behaviour decreasing in young adolescents?

OBJECTIVE: To report trends in underweight, overweight and obesity in 12-15-year-old adolescents and examine changes in dieting behaviour, which have been less well documented. DESIGN: Comparison of two independent representative cross-sectional surveys. SETTING: Northern Ireland. SUBJECTS: Weight and height were objectively measured in 1324 boys and 1160 girls in 1996 and 1274 boys and 1374 girls in 2007. Participants reported whether they were following any particular diet including a self-proposed or prescribed weight-reduction diet. RESULTS: Overweight and obesity increased in girls from 15 % to 23 % and 2 % to 6 %, respectively. Increases were more modest in boys with overweight increasing from 13 % to 18 % and obesity from 3 % to 6 %. The proportion of underweight adolescents decreased from 9 % to 6 % in girls and 8 % to 5 % in boys. Evidence of social disparity was observed in girls from a manual socio-economic background, with overweight/obesity prevalence rates increasing from 21 % to 36 % compared with 15 % to 26 % in girls from a non-manual background. Despite these trends fewer adolescents, in particular girls, reported following weight-reduction diets (14 % of overweight/obese girls in 2007 v. 21 % in 1996; 8 % of boys in 2007 v. 13 % in 1996). Of these girls, the proportion from a manual background following weight-reduction diets decreased from 25 % to 11 %. CONCLUSIONS: Overweight and obesity are continuing to increase in adolescents despite government and media awareness strategies. There also appears to be reduced dieting behaviour, despite increasing body weight, particularly in girls from manual socio-economic backgrounds.

Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease.

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10(-24)). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10(-9)) and AGBL1 (rs2469184, p = 3.61 × 10(-8)). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10(-56)) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10(-13)). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ∼29% of the variance in aPTT and two loci that account for ∼14% of the variance in PT were detected and supported by functional data.

Status of novel cardiovascular risk factor and cardiovascular disease risk in an urban Cuban population--a pilot study.

Cardiovascular disease is the main cause of death in Cuba, yet the prevalence of novel risk factors is not known. To examine the prevalence of risk factors of traditional and novel cardiovascular diseases (CVDs) among an urban Cuban population, a cross-sectional pilot survey was undertaken in Havana city, Cuba. Ninety-seven adults aged 45-60 years registered to receive medical care at a policlinic. The prevalences of rates of CVD risk factors were: hypertension (> or =140/90 mmHg) (53.6%), hypercholesterolaemia (total cholesterol >5.2 mmol/L) (47.0%), low high-density lipoprotein (HDL)-cholesterol (<1.03 mmol/L) (64.3%); diabetes (self-reported) (24.6%); metabolic syndrome (ATP III criteria) (58.2%); overweight and obesity (body mass index > or = 25 kg/m2) (78.0%); current smoking (39.3%); elevated level of C-reactive protein (3 15 micromol/L) (11.1%). The total carotenoid status was independently associated with waist-circumference and risk of diabetes and metabolic syndrome. In this small unrepresentative sample of people aged 40-65 years from Havana city, there was a high prevalence of traditional and novel CVD risk factors. The total serum carotenoid status appeared to be associated with an increased prevalence of CVD risk factors.

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.

The stroke offspring study: is parental stroke history of value in targeted risk factor screening?

AIM: This study aimed to compare the prevalence of stroke risk factors among people with a parental history of stroke to those in a control group of individuals, of similar age, gender and social class, with no parental stroke history. BACKGROUND: Parental stroke increases an individual's risk of stroke, but little is known of the potential value of using this information in targeted screening for primary prevention in general practice. METHOD: We sent questionnaires to 300 randomly selected individuals aged 40-65 years, in each of 11 different general practices in Northern Ireland. Among 1061 responses received within six weeks, 332 reported a parental history of stroke (31.3%). We matched respondents with (cases) and without (controls) a parental history of stroke on characteristics of age, gender and socioeconomic status. Matched pairs were invited to attend a consultation at which their diet and exercise habits were assessed using validated questionnaires and height, weight, blood pressure and serum lipids and glucose were measured. FINDINGS: Matched data were available for 199 case-control pairs (398 individuals). Mean systolic and diastolic blood pressures were significantly higher in cases than in paired controls (systolic 146.3 versus 140.6 mmHg (P < 0.01); diastolic 87.7 versus 85.0 mmHg (P = 0.014)). Cases consumed more alcohol than their paired controls (13.8 versus 10.1 U/week (P < 0.01)), but their measures of body mass index, lipids, diabetes, diet and exercise did not differ significantly. The results of this study suggest that screening offspring of patients with stroke in respect of blood pressure has potential value in identifying people likely to benefit from primary prevention, but do not support the adoption of a targeted screening strategy for other commonly cited stroke risk factors.

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.

The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: the Caerphilly Study.

OBJECTIVES: Interleukin-6 (IL-6) is a key pro-inflammatory cytokine which mediates expression of several 'downstream' inflammatory markers and may play a role in atherothrombosis. However, it is not yet known whether IL-6 plays a role in mediating the associations of each marker with risk of coronary heart disease (CHD) or ischaemic stroke (IS). METHODS AND RESULTS: We examined the role of IL-6 and several "downstream" markers of inflammation (leucocyte counts, plasma and serum viscosity, fibrinogen, C-reactive protein, alpha1-antitrypsin and alpha2-macroglobulin) with risk of subsequent CHD, IS, and a combined endpoint (CHD/IS) in a population of British men. 2208 men aged 45-64 years were followed for a median of 13.4 years and 486 men had experienced a cardiovascular event. In age-adjusted analyses, most inflammatory markers were significantly associated with risk of CHD or CHD/IS, but for IS associations were weaker. On multivariable analyses, including conventional risk factors, associations of serum viscosity, alpha2-macroglobulin and leucocyte count became non-significant for CHD and CHD/IS, while no inflammatory marker retained a significant association with risk of IS. In contrast, IL-6 retained a significant association with CHD and CHD/IS and, after adjustment for IL-6, hazard ratios for downstream inflammatory markers were attenuated to non-significance. CONCLUSIONS: These findings suggest that IL-6 may play a role in mediating the associations of circulating inflammatory markers with risk of CHD in men. Further studies are required to assess whether this is also the case for risk of IS, and for CHD/IS in women.

The association of C-reactive protein and CRP genotype with coronary heart disease: findings from five studies with 4,610 cases amongst 18,637 participants.

BACKGROUND: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association. METHODS AND RESULTS: We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N = 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95%CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I(2) = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I(2)<7.5%, p>0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80). CONCLUSIONS: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.

Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations.

A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine beta-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 micromol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele 'normalizes' homocysteine and folate levels in MTHFR 677TT individuals.

Is vigorous physical activity contraindicated in subjects with coronary heart disease? Evidence from the Caerphilly study.

AIMS: A large study of British civil servants reported that, in men with electrocardiogram ischaemia but no symptoms, vigorous habitual leisure activity might be associated with increased subsequent risk of myocardial infarction (MI). We examine this for MI and stroke in a general population of British men. METHODS AND RESULTS: Between 1984 and 1988, 2398 middle-aged men were recruited into the cohort in Caerphilly, South Wales, UK. Physical activities during leisure and at work were assessed by validated questionnaires. Follow-up was for 12 years, and both fatal and non-fatal cardiovascular events (MI, stroke or MI, and stroke) were recorded. After adjustment for age and other confounders, men in the highest third of vigorous physical activity experienced decreased risk of MI, relative to men in the lowest third; hazard ratios (HR) (95% CI) were 0.71 (0.50, 1.03), 0.42 (0.19, 0.92), and 0.60 (0.38, 0.94) in men with symptomatic, asymptomatic coronary heart disease (CHD), and no evidence of CHD at baseline, respectively. HRs for stroke were non-significantly raised for subjects with asymptomatic CHD (1.36 (0.47, 3.91). CONCLUSION: Habitual vigorous activity was not associated with increased risk of subsequent MI in subjects with established CHD, but additional data for stroke would be useful.

Thiol and cardiovascular risk factor status in a male northern Irish population.

OBJECTIVES: Raised plasma homocysteine is a risk factor for cardiovascular disease (CVD). Cysteine has also been associated with CVD risk. In this study, we investigated the association between known CVD risk factors, dietary factors, and total plasma cysteine, cysteinyl-glycine, and homocysteine. METHODS: The study group was 765 male workers aged between 30-49 years. The dietary habits of the subjects were recorded using a food frequency questionnaire. Body mass index (BMI), smoking status, and blood pressure were assessed, and fasting blood samples were taken for analysis of serum concentrations of vitamins, lipids, total plasma cysteine, cysteinyl-glycine, and homocysteine, and genotyping for the methylenetetrahydrofolate reductase (MTHFR) polymorphism. RESULTS: In multivariable analyses, cysteine was significantly positively associated with age and negatively associated with serum vitamin B12 and serum vitamin B6, while cysteinyl-glycine was significantly positively associated with BMI. Homocysteine (tHcy) was significantly negatively associated with serum folate, serum vitamin B12, and fruit and vegetable intake, and also depended on the MTHFR 677C>T genotype. CONCLUSIONS: Our data show a significant relationship between age, serum levels of B-vitamins and cysteine, and BMI and cysteinyl-glycine. In agreement with other studies, we also confirm an association between tHcy, serum folate and vitamin B12, MTHFR genotype, and fruit and vegetable intake. Further investigation into the role of these thiols and their determinants in CVD is required.

Lycopene status is not associated with insulin-like growth factor-1 concentration in a healthy male population.

OBJECTIVE: The aim of this study was to assess the relationship between lycopene and insulin-like growth factor-1 levels in a healthy male population. DESIGN: Insulin-like growth factor-1 status was assessed in healthy men aged 30-49 years (n = 104) with either high or low lycopene concentrations. RESULTS: There was no significant difference between insulin-like growth factor-1 levels in the high- and low-lycopene groups; high lycopene group; 8.21 (2.73) nmol/L; low lycopene group; 7.65 (2.14) nmol/L, p = 0.46 (Mean (SD)). CONCLUSIONS: In this small observational study, no association was found between lycopene concentration and insulin-like growth factor-1 concentration.

Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME).

BACKGROUND: Classic coronary heart disease risk factors fail to explain the large coronary heart disease incidence gradient between Northern Ireland and France. The Prospective Epidemiological Study of Myocardial Infarction (PRIME), a multicentre prospective study of 10593 men, aims to investigate novel risk factors in these populations. We tested the hypothesis that higher bilirubin, a bile pigment possessing antioxidant properties, is associated with decreased coronary heart disease risk. METHODS: Bilirubin was measured in 216 participants who had developed coronary heart disease at 5-year follow-up and in 434 matched controls. RESULTS: Bilirubin was significantly lower in cases (geometric mean 7.95 micromol/l; interquartile range 5.32-12.33 micromol/l) compared with controls (9.07; 6.16-12.76; P=0.005). Conditional logistic regression, adjusted for classical and putative risk factors, showed a U-shaped pattern, with coronary heart disease risk significantly lower for bilirubin in the third and fourth fifths, compared with the first. Additionally, there was a significant quadratic relationship between coronary heart disease risk and fifths of bilirubin concentration (chi2=6.80, df=2; P=0.035). CONCLUSIONS: These findings suggest that bilirubin is a novel coronary heart disease risk marker in middle-aged men, with a U-shaped relationship observed between bilirubin concentration and coronary heart disease risk.

Lack of association between serological evidence of past Coxiella burnetii infection and incident ischaemic heart disease: nested case-control study.

BACKGROUND: Coxiella burnetii causes the common worldwide zoonotic infection, Q fever. It has been previously suggested that patients who had recovered from acute Q fever (whether symptomatic or otherwise) may be at increased risk of ischaemic heart disease. We undertook this study to determine if past infection with Coxiella burnetii, the aetiological agent of Q fever, is a risk factor for the subsequent development of ischaemic heart disease. METHODS: A nested case-control study within the Prospective Epidemiological Study of Myocardial Infarction (PRIME). The PRIME study is a cohort study of 10,593 middle-aged men undertaken in France and Northern Ireland in the 1990s. A total of 335 incident cases of ischaemic heart disease (IHD) were identified and each case was matched to 2 IHD free controls. Q fever seropositivity was determined using a commercial IgG ELISA method. RESULTS: Seroprevalence of Q fever in the controls from Northern Ireland and France were 7.8% and 9.0% respectively. No association was seen between seropositivity and age, smoking, lipid levels, or inflammatory markers. The unadjusted odds ratio (95% CI) for Q fever seropositivity in cases compared to controls was 0.95 (0.59, 1.57). The relationship was substantially unaltered following adjustment for cardiovascular risk factors and potential confounders. CONCLUSION: Serological evidence of past infection with C. burnetii was not found to be associated with an increased risk of IHD.

Breast feeding and cardiovascular disease risk factors, incidence, and mortality: the Caerphilly study.

STUDY OBJECTIVE: To investigate the association of having been breast fed with cardiovascular disease risk factors, incidence, and mortality. DESIGN: Prospective cohort study. SETTING: Caerphilly, South Wales. PARTICIPANTS: All men aged 45-59 years living in and around the study area. Of 2818 eligible men, 2512 (89%) were seen. Altogether 1580 men (63%) obtained details of how they had been fed in infancy (ever breast fed or only bottle fed) from their mother or a close female relative. A subset of 1062 subjects reported on whether bottle fed or the duration of breast feeding if breast fed. MAIN RESULTS: Breast feeding was not associated with stature, blood pressure, insulin resistance, total cholesterol, or fibrinogen. In fully adjusted models (controlling for age, birth order, and social position in childhood and adulthood), breast feeding was associated with greater body mass index than bottle feeding (difference: 0.41 kg/m(2) (95% CI: 0.01 to 0.81). There was a positive association between breast feeding and coronary heart disease mortality (hazard ratio: 1.73; 1.17 to 2.55) and incidence (1.54; 1.17 to 2.04) (fully adjusted models). There was no evidence of a duration-response effect, which might be expected if an adverse effect of breast feeding was causal. CONCLUSION: These data provide little evidence of a protective influence of breast feeding on cardiovascular disease risk factors, incidence, or mortality. A possible adverse effect of breast feeding on coronary heart disease incidence was observed but may have a number of explanations, including selection and information bias. In view of these limitations, further long term studies with improved measures of infant feeding are required to confirm or refute these findings.

Resonance-thrombography indices of the haemostatic process in relation to risk of incident coronary heart disease: 9 years follow-up in the Caerphilly Prospective Heart Disease Study.

Global assays, such as resonance-thrombography (RTG), which measure the interaction between platelets, coagulation and fibrinolysis have been used as summary measures of risk for over two decades but have not been evaluated in epidemiological studies. We examined whether RTG indices are risk indicators for incident coronary heart disease (CHD). RTG indices, related haematological variables and other risk factors were measured between 1984 and 1988 in a cohort of 2398 British men. Reaction time (r) and amplitude of fibrin leg (AF) were associated with lifestyle risk factors. During 9 years of follow-up, 282 (12%) men developed a major new CHD event, as classified by World Health Organization criteria. On adjustment for age, only r and AF measured at baseline were related to risk of incident CHD. On multivariate adjustment in a multiple logistic regression model that included age, diastolic blood pressure, body mass index, total and high-density lipoprotein cholesterol, lifestyle risk factors and use of prescribed medicine, these associations weakened but remained significant. Additional adjustment for fibrinogen, viscosity, white cell count and fibrin d-dimer either reduced these associations to non-significance (AF) or to borderline significance (r).

The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine.

Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P = 0.001) but not in non-smokers (P = 0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P = 0.003) but not light smokers (P = 0.09), in men (P = 0.003) but not women (P = 0.11), and in subjects from the lowest serum folate quartile (P = 0.49) but not from folate quartiles 2-4 (P = 0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.