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Background: The associations between height, socioeconomic position (SEP) and coronary heart disease (CHD) incidence are well established, but the contribution of genetic factors to these associations is still poorly understood. We used a polygenic score (PGS) for height to shed light on these associations., Methods: Finnish population-based health surveys in 1992-2011 (response rates 65-93%) were linked to population registers providing information on SEP and CHD incidence up to 2019. The participants (N=29 996; 54% women) were aged 25-75 at baseline, and there were 1767 CHD incident cases (32% in women) during 472 973 person years of follow-up. PGS-height was calculated based on 33 938 single-nucleotide polymorphisms, and residual height was defined as the residual of height after adjusting for PGS-height in a linear regression model. HRs of CHD incidence were calculated using Cox regression., Results: PGS-height and residual height showed clear gradients for education, social class and income, with a larger association for residual height. Residual height also showed larger associations with CHD incidence (HRs per 1 SD 0.94 in men and 0.87 in women) than PGS-height (HRs per 1 SD 0.99 and 0.97, respectively). Only a small proportion of the associations between SEP and CHD incidence was statistically explained by the height indicators (6% or less)., Conclusions: Residual height associations with SEP and CHD incidence were larger than for PGS-height. This supports the role of material and social living conditions in childhood as contributing factors to the association of height with both SEP and CHD risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Accurate measurement of the effects of disease status on healthcare costs is important in the pragmatic evaluation of interventions but is complicated by endogeneity bias. Mendelian Randomization, the use of random perturbations in germline genetic variation as instrumental variables, can avoid these limitations. We used a novel Mendelian Randomization analysis to model the causal impact on inpatient hospital costs of liability to six prevalent diseases and health conditions: asthma, eczema, migraine, coronary heart disease, Type 2 diabetes, and depression. We identified genetic variants from replicated genome-wide associations studies and estimated their association with inpatient hospital costs on over 300,000 individuals. There was concordance of findings across varieties of sensitivity analyses, including stratification by sex and methods robust to violations of the exclusion restriction. Results overall were imprecise and we could not rule out large effects of liability to disease on healthcare costs. In particular, genetic liability to coronary heart disease had substantial impacts on costs., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease., Methods: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases., Results: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered., Conclusions: Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Taller people have a lower risk of coronary heart disease but a higher risk of many cancers. Mendelian randomization (MR) studies in unrelated individuals (population MR) have suggested that these relationships are potentially causal. However, population MR studies are sensitive to demography (population stratification, assortative mating) and familial (indirect genetic) effects., Methods: In this study, we performed within-sibship MR analyses using 78,988 siblings, a design robust against demography and indirect genetic effects of parents. For comparison, we also applied population MR and estimated associations with measured height., Results: Within-sibship MR estimated that 1 SD taller height lowers the odds of coronary heart disease by 14% (95% CI: 3-23%) but increases the odds of cancer by 18% (95% CI: 3-34%), highly consistent with population MR and height-disease association estimates. There was some evidence that taller height reduces systolic blood pressure and low-density lipoprotein cholesterol, which may mediate some of the protective effects of taller height on coronary heart disease risk., Conclusions: For the first time, we have demonstrated that the purported effects of height on adulthood disease risk are unlikely to be explained by demographic or familial factors, and so likely reflect an individual-level causal effect. Disentangling the mechanisms via which height affects disease risk may improve the understanding of the etiologies of atherosclerosis and carcinogenesis., Funding: This project was conducted by researchers at the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and also supported by a Norwegian Research Council Grant number 295989., Competing Interests: LH, BB, HR, BÅ, GD, ND No competing interests declared, (© 2022, Howe et al.)

Background: Depression is a risk factor for coronary heart disease (CHD), but less is known whether genetic susceptibility to CHD or regional-level social indicators modify this association., Methods: Risk factors of CHD including a Polygenic Risk Score (PRS) were measured for 19 999 individuals residing in Finland in 1997, 2002, 2007 and 2012 (response rates 60%-75%). During the register-based follow-up until 2015, there were 1381 fatal and non-fatal incident CHD events. Unemployment rate, degree of urbanisation and crime rate of the municipality of residence were used as regional level social indicators. HRs were calculated using register-based antidepressant purchases as a non-reversible time-dependent covariate., Results: Those having depression and in the highest quartile of PRS had somewhat higher CHD risk than predicted only by the main effects of depression and PRS (HR for interaction 1.53, 95% CI 0.95 to 2.45). Depression was moderately associated with CHD in high crime (HR 1.51, 95% CI 1.20 to 1.90) and weakly in low crime regions (HR 1.07, 95% CI 0.86 to 1.33; p value of interaction=0.087). Otherwise, we did not found evidence for interactions., Conclusions: Those having both depression and high genetic susceptibility need a special attention in healthcare for CHD., Competing Interests: Competing interests: VS reports personal fees from Novo Nordisk and Sanofi for consulting and grants from Bayer outside this work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding., Research Design and Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment., Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs., Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes., (© 2020 by the American Diabetes Association.)

Background: Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD., Methods and Findings: We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10-8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10-8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components., Conclusions: These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BAF reports receiving grants from Amgen, Merck & Co., Novartis, and Esperion Therapeutics; consulting or advisory board fees from Amgen, Regeneron, Sanofi, Merck & Co., Pfizer, CiVi BioPhama, and KrKA Pharmaceuticals; and grants from Merck & Co., Amgen, Novartis, Novo Nordisk, Regeneron, Sanofi, Pfizer, Eli Lilly, Mylan, Ionis, dalCOR, Silence Therapeutics, Integral Therapeutics, CiVi Pharma, KrKa Phamaceuticals, American College of Cardiology, European Atherosclerosis Society, and European Society of Cardiology. MVH has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the The Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. GDS is an Academic Editor on PLOS Medicine's editorial board. All other authors report no potential conflicts of interest.

In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of 'good cholesterol', strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies-that began to appear at the same time as the initial negative randomized controlled trials-made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure-such as that with respect to vitamin E supplementation and CHD risk-rather than pass them over in silence., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies., Competing Interests: The authors have declared that no competing interests exist.

Background: Two-sample summary-data Mendelian randomization (MR) incorporating multiple genetic variants within a meta-analysis framework is a popular technique for assessing causality in epidemiology. If all genetic variants satisfy the instrumental variable (IV) and necessary modelling assumptions, then their individual ratio estimates of causal effect should be homogeneous. Observed heterogeneity signals that one or more of these assumptions could have been violated., Methods: Causal estimation and heterogeneity assessment in MR require an approximation for the variance, or equivalently the inverse-variance weight, of each ratio estimate. We show that the most popular 'first-order' weights can lead to an inflation in the chances of detecting heterogeneity when in fact it is not present. Conversely, ostensibly more accurate 'second-order' weights can dramatically increase the chances of failing to detect heterogeneity when it is truly present. We derive modified weights to mitigate both of these adverse effects., Results: Using Monte Carlo simulations, we show that the modified weights outperform first- and second-order weights in terms of heterogeneity quantification. Modified weights are also shown to remove the phenomenon of regression dilution bias in MR estimates obtained from weak instruments, unlike those obtained using first- and second-order weights. However, with small numbers of weak instruments, this comes at the cost of a reduction in estimate precision and power to detect a causal effect compared with first-order weighting. Moreover, first-order weights always furnish unbiased estimates and preserve the type I error rate under the causal null. We illustrate the utility of the new method using data from a recent two-sample summary-data MR analysis to assess the causal role of systolic blood pressure on coronary heart disease risk., Conclusions: We propose the use of modified weights within two-sample summary-data MR studies for accurately quantifying heterogeneity and detecting outliers in the presence of weak instruments. Modified weights also have an important role to play in terms of causal estimation (in tandem with first-order weights) but further research is required to understand their strengths and weaknesses in specific settings., (© The Author(s) 2018. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies., Methods and Findings: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models., Conclusions: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies., Competing Interests: BMP reports serving on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. WK reports personal fees from AstraZeneca Novartis, Pfizer, The Medicines Company, GlaxoSmithKline, DalCor, Sanofi, Berlin-Chemie, Kowa, and Amgen. WK also reports grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex. All reports from WK are outside the submitted work. WM reports grants and personal fees from Siemens Diagnostics, Aegerion Pharmaceuticals, AMGEN, AstraZeneca, Danone Research, Sanofi/Genzyme, Pfizer, BASF, and Numares. WM reports personal fees from Hoffmann LaRoche, MSD, Sanofi, and Alexion. WM is employed by Synlab Holding Deutschland GmbH and all reports by WM are outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear., Objectives: The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood., Methods: BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children., Results: Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index., Conclusions: The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets, but this has yet to be realized at a level reflecting expectation. One reason for this, we suggest, is that GWAS, to date, have generally not focused on phenotypes that directly relate to the progression of disease and thus speak to disease treatment.

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease., Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits., Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m 2 ; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD)., Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity., (© 2017 American Heart Association, Inc.)

Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis., Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D., Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index ( P  < 0.001), triglycerides ( P  < 0.001), non high-density (non-HDL) cholesterol ( P  < 0.001), C-reactive protein ( P  = 0.042), and systolic blood pressure ( P  = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity ( P  < 0.001 for both)., Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Objective: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease., Design: Mendelian randomisation meta-analysis of 56 epidemiological studies., Participants: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers., Main Outcome Measures: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption., Results: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95))., Conclusions: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health., (© Holmes et al 2014.)

Aims: To explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors., Methods and Results: We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (-4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [-2.0% (-2.1, -1.8)] was not present in the IV analyses [0.6% (-3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [-0.13 kg/m(2) (-0.16, -0.10)] and with triglycerides [-0.4% (-0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m(2) (0.59, 2.15)] and the strong inverse association with triglycerides [-14.9% (-25.6, -4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose., Conclusion: Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.

Objective: This study uses a prospective design to examine the association between self-reported job insecurity and incident coronary heart disease; an association which has been little investigated previously., Methods: Participants were 4174 British civil servants (1236 women and 2938 men), aged 42 to 56 with self-reported data on job insecurity and free from coronary heart disease at baseline (1995-6). These participants were followed until 2002-4, an average of 8.6 years, for incident fatal coronary heart disease, clinically verified incident non-fatal myocardial infarction, or definite angina (a total of 168 events)., Results: Cox proportional hazard models adjusted for socio-demographic characteristics showed job insecurity to be associated with a 1.42-fold (95% CI, 1.05-1.93) risk of incident coronary heart disease compared with secure employment. Adjustment for physiological and behavioral cardiovascular risk factors had little effect on this estimate; 1.38 (1.01-1.88)., Conclusion: This study suggests that job insecurity may adversely affect coronary health., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Adult height is known to be inversely related to coronary heart disease (CHD) risk. We sought to investigate transgenerational influence of parental height on offspring's CHD risk., Methods: Parents took part in a cardiorespiratory disease survey in two Scottish towns during the 1970s, in which their physical stature was measured. In 1996, their offspring were invited to participate in a similar survey, which included an electrocardiogram recording and risk factor assessment., Results: A total of 2306 natural offspring aged 30-59 years from 1456 couples were subsequently flagged for notification of mortality and followed for CHD-related hospitalizations. Taller paternal and/or maternal height was associated with socio-economic advantage, heavier birthweight and increased high-density lipoprotein cholesterol in offspring. Increased height in fathers, but more strongly in mothers (risk ratio for 1 SD change in maternal height = 0.85; 95% confidence interval: 0.76 to 0.95), was associated with a lower risk of offspring CHD, adjusting for age, sex, other parental height and CHD risk factors., Conclusion: There is evidence of an association between taller parental, particularly maternal, height and lower offspring CHD risk. This may reflect an influence of early maternal growth on the intrauterine environment provided for her offspring.

Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling., Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6., Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes., Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease., Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: To examine explanations for the higher rates of male mortality in two Scottish cohorts compared with a cohort in south-east England for which similar data were collected., Methodology/principal Findings: We compared three cohort studies which recruited participants in the late 1960s and early 1970s. A total of 13,884 men aged 45-64 years at recruitment in the Whitehall occupational cohort (south-east England), 3,956 men in the Collaborative occupational cohort and 6,813 men in the Renfrew & Paisley population-based study (both central Scotland) were included in analyses of all-cause and cause-specific mortality. All-cause mortality was 25% (age-adjusted hazard ratio 1.25, 95% confidence interval (CI)1.21 to 1.30) and 41% (hazard ratio 1.41 (95% CI 1.36 to 1.45) higher in the Collaborative and Renfrew & Paisley cohorts respectively compared to the Whitehall cohort. The higher mortality rates were substantially attenuated by social class (to 8% and 17% higher respectively), and were effectively eliminated upon the further addition of the other baseline risk factors, such as smoking habit, lung function and pre-existing self-reported morbidity. Despite this, coronary heart disease mortality remained 11% and 16% higher, stroke mortality 45% and 37% higher, mortality from accidents and suicide 51% and 70% higher, and alcohol-related mortality 46% and 73% higher in the Collaborative and Renfrew & Paisley cohorts respectively compared with the Whitehall cohort in the fully adjusted model., Conclusions/significance: The higher all-cause, respiratory, and lung cancer male mortality in the Scottish cohorts was almost entirely explained by social class differences and higher prevalence of known risk factors, but reasons for the excess mortality from stroke, alcohol-related causes, accidents and suicide remained unknown.

Objective: To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease., Design: Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries., Participants: 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors., Main Outcome Measures: Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals., Results: CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference)., Conclusion: Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.

Background: Multiple risk factor interventions using counselling and educational methods assumed to be efficacious and cost-effective in reducing coronary heart disease (CHD) mortality and morbidity and that they should be expanded. Trials examining risk factor changes have cast doubt on the effectiveness of these interventions., Objectives: To assess the effects of multiple risk factor interventions for reducing total mortality, fatal and non-fatal events from CHD and cardiovascular risk factors among adults assumed to be without prior clinical evidence CHD.., Search Strategy: We updated the original search BY SEARCHING CENTRAL (2006, Issue 2), MEDLINE (2000 to June 2006) and EMBASE (1998 to June 2006), and checking bibliographies., Selection Criteria: Randomised controlled trials of more than six months duration using counselling or education to modify more than one cardiovascular risk factor in adults from general populations, occupational groups or specific risk factors (i.e. diabetes, hypertension, hyperlipidaemia, obesity)., Data Collection and Analysis: Two authors extracted data independently. We expressed categorical variables as odds ratios (OR) with 95% confidence intervals (CI). Where studies published subsequent follow-up data on mortality and event rates, we updated these data., Main Results: We found 55 trials (163,471 participants) with a median duration of 12 month follow up. Fourteen trials (139,256 participants) with reported clinical event endpoints, the pooled ORs for total and CHD mortality were 1.00 (95% CI 0.96 to 1.05) and 0.99 (95% CI 0.92 to 1.07), respectively. Total mortality and combined fatal and non-fatal cardiovascular events showed benefits from intervention when confined to trials involving people with hypertension (16 trials) and diabetes (5 trials): OR 0.78 (95% CI 0.68 to 0.89) and OR 0.71 (95% CI 0.61 to 0.83), respectively. Net changes (weighted mean differences) in systolic and diastolic blood pressure (53 trials) and blood cholesterol (50 trials) were -2.71 mmHg (95% CI -3.49 to -1.93), -2.13 mmHg (95% CI -2.67 to -1.58 ) and -0.24 mmol/l (95% CI -0.32 to -0.16), respectively. The OR for reduction in smoking prevalence (20 trials) was 0.87 (95% CI 0.75 to 1.00). Marked heterogeneity (I(2) > 85%) for all risk factor analyses was not explained by co-morbidities, allocation concealment, use of antihypertensive or cholesterol-lowering drugs, or by age of trial., Authors' Conclusions: Interventions using counselling and education aimed at behaviour change do not reduce total or CHD mortality or clinical events in general populations but may be effective in reducing mortality in high-risk hypertensive and diabetic populations. Risk factor declines were modest but owing to marked unexplained heterogeneity between trials, the pooled estimates are of dubious validity. Evidence suggests that health promotion interventions have limited use in general populations.

Objective: Limited evidence suggests NT-proBNP improves prediction of coronary heart disease (CHD) events but further data are needed, especially in people without pre-existing CHD and in women., Methods: We measured NT-proBNP in serum from 162 women with incident CHD events and 1226 controls (60-79 years) in a case-control study nested within the prospective British Women's Heart and Health Study. All cases and controls were free from CHD at baseline. We related NT-proBNP to CHD event risk, and determined to what extent NT-proBNP enhanced CHD risk prediction beyond established risk factors., Results: The odds ratio for CHD per 1 standard deviation increase in log(e)NT-proBNP was 1.37 (95% CI: 1.13-1.68) in analyses adjusted for established CHD risk factors, social class, CRP and insulin. However, addition of log(e)NT-proBNP did not improve the discrimination of a prediction model including age, social class, smoking, physical activity, lipids, fasting glucose, waist:hip ratio, hypertension, statin and aspirin use, nor a standard Framingham risk score model; area under the receiver operator curve for the former model increased from 0.676 to 0.687 on inclusion of NT-proBNP (p=0.3). Furthermore, adding NT-proBNP did not improve calibration of a prediction model containing established risk factors, nor did inclusion more appropriately re-classify participants in relation to their final outcome. Findings were similar (independent associations, but no prediction improvement) for fasting insulin and CRP., Conclusion: These results caution against use of NT-proBNP for CHD risk prediction in healthy women and suggest a need for larger studies in both genders to resolve outstanding uncertainties.

Context: Adiponectin levels appear weakly linked to incident vascular disease, but the high molecular weight (HMW) fraction may be more relevant., Objective: Our objective was to test whether HMW adiponectin, the key biologically active fraction, is linked to incident coronary heart disease (CHD) events. DESIGN, PARTICIPANTS, AND MAIN OUTCOME MEASURES: We assessed the association between HMW adiponectin (measured by ELISA) and CHD risk in a prospective (4-yr) case-control study nested within the British Women's Heart and Health Study. All women were postmenopausal., Setting: Women were seen in a primary care setting., Results: Among both cases (n = 167) and controls (n = 333), HMW adiponectin positively correlated with age and high-density lipoprotein cholesterol and inversely correlated with waist to hip ratio, fasting insulin, fasting glucose, homeostasis model assessment for insulin resistance scores, C-reactive protein, and triglycerides, in similar fashion to total adiponectin. The age-adjusted relative risk ratio for a doubling of HMW adiponectin was 0.96 (95% confidence interval, 0.78-1.18), and adjustment for any of the potential confounding or mediating variables did not substantively alter this. Additional adjustments for childhood social class, alcohol consumption, hormone replacement therapy use, statin, aspirin, or blood pressure medication did not alter the null association. When we examined the effect of HMW adiponectin by quarters of its distribution, there was no evidence of any associations (P trend = 0.71). There was also no association of the ratio of HMW adiponectin to total adiponectin with CHD risk; age-adjusted relative risk per doubling of the ratio was 1.10 (95% confidence interval, 0.80-1.50)., Conclusions: Despite associations with total adiponectin and insulin resistance, our data go against any apparent association between HMW adiponectin levels and incident CHD events.

The alcohol dehydrogenase 1C gene (ADH1C) gamma2gamma2 variant reportedly interacts with moderate alcohol consumption to increase HDL-cholesterol levels and reduce coronary heart disease (CHD). We undertook replication studies in two large population cohorts of women and men. 3234 women and 1313 men with relevant genotypic and phenotypic data from two prospective population cohorts were genotyped for ADH1C variants. No association was found between ADH1C variants and HDL-cholesterol, blood pressure or incident CHD, although ADH1C was associated with alcohol consumption. There was no evidence of interactions between ADH1C variants and moderate alcohol intake on HDL-cholesterol, blood pressure or CHD incidence. Life-long women abstainers had adverse risk factor profiles. Our findings do not support the hypothesis that ADH1C variants are associated with CHD risk in people who drink moderately.

Objectives: We examined the associations between socioeconomic position, co-occurrence of behavior-related risk factors, and the effect of these factors on the relative and absolute socioeconomic gradients in coronary heart disease., Methods: We obtained the socioeconomic position of 9337 men and 39,255 women who were local government employees aged 17-65 years from employers' records (the Public Sector Study, Finland). A questionnaire survey in 2000-2002 was used to collect data about smoking, heavy alcohol consumption, physical inactivity, obesity, and prevalence of coronary heart disease (myocardial infarction or angina diagnosed by a doctor)., Results: The age-adjusted odds of coronary heart disease were 2.1-2.2 times higher for low-income groups than high-income groups for both men and women, and adjustment for risk factors attenuated these associations by 13%-29%. There was no further attenuation with additional adjustment for the number of co-occurring risk factors, although socioeconomic disadvantage was associated with the co-occurrence of multiple risk factors. The absolute difference in coronary heart disease risk between socioeconomic groups could not be attributed to the measured risk factors., Conclusions: Interventions to reduce adult behavior-related risk factors may not completely remove socioeconomic differences in relative or absolute coronary heart disease risk, although they would lessen these effects.

Background: Primary prevention programmes in many countries attempt to reduce mortality and morbidity due to coronary heart disease (CHD) through risk factor modification. It is widely believed that multiple risk factor intervention using counselling and educational methods is efficacious and cost-effective and should be expanded. Recent trials examining risk factor changes have cast considerable doubt on the effectiveness of these multiple risk factor interventions., Objectives: To assess the effects of multiple risk factor intervention for reducing cardiovascular risk factors, total mortality, and mortality from CHD among adults without clinical evidence of established cardiovascular disease., Search Strategy: MEDLINE was searched for the original review to 1995. This was updated by searching the Cochrane Central Register of Controlled Trials on The Cochrane Library Issue 3 2001, MEDLINE (2000 to September 2001) and EMBASE (1998 to September 2001)., Selection Criteria: Intervention studies using counselling or education to modify more than one cardiovascular risk factor in adults from general populations, occupational groups, or high risk groups. Trials of less than 6 months duration were excluded., Data Collection and Analysis: Data were extracted by two reviewers independently. Investigators were contacted to obtain missing information., Main Results: A total of 39 trials were found of which ten reported clinical event data. In the ten trials with clinical event end-points, the pooled odds ratios for total and CHD mortality were 0.96 (95% confidence intervals (CI) 0.92 to 1.01) and 0.96 (95% CI 0.89 to 1.04) respectively. Net changes in systolic and diastolic blood pressure, and blood cholesterol were (weighted mean differences) -3.6 mmHg (95% CI -3.9 to -3.3 mmHg), -2.8 mmHg (95% CI -2.9 to -2.6 mmHg) and -0.07 mMol/l (95% CI -0.8 to -0.06 mMol/l) respectively. Odds of reduction in smoking prevalence was 20% (95% CI 8% to 31%). Statistical heterogeneity between the studies with respect to mortality and risk factor changes was due to trials focusing on hypertensive participants and those using considerable amounts of drug treatment., Authors' Conclusions: The pooled effects suggest multiple risk factor intervention has no effect on mortality. However, a small, but potentially important, benefit of treatment (about a 10% reduction in CHD mortality) may have been missed. Risk factor changes were relatively modest, were related to the amount of pharmacological treatment used, and in some cases may have been over-estimated because of regression to the mean effects, lack of intention to treat analyses, habituation to blood pressure measurement, and use of self-reports of smoking. Interventions using personal or family counselling and education with or without pharmacological treatments appear to be more effective at achieving risk factor reduction and consequent reductions in mortality in high risk hypertensive populations. The evidence suggests that such interventions have limited utility in the general population.

Objective: To examine the relations between obesity or overweight and coronary heart disease (CHD) mortality in men with and without prevalent CHD in a prospective cohort study., Methods: In the Whitehall study of London-based male government employees, 18 403 middle age men were followed up for a maximum of 35 years having participated in a medical examination in the late 1960s in which weight, height, CHD status, and a range of other social, physiological, and behavioural characteristics were measured., Results: In age-adjusted analyses of men with baseline CHD there was a modest raised risk in the overweight relative to normal weight groups for all cause mortality (hazard ratio 1.10, 95% confidence interval (CI) 1.00 to 1.20) and CHD mortality (1.28, 95% CI 1.11 to 1.47) but not for stroke mortality (1.01, 95% CI 0.73 to 1.40). Mortality was similarly raised in the obese group. While these slopes were much steeper in men who were apparently CHD-free at study induction, the difference in the gradients according to baseline CHD status did not attain significance at conventional levels (p value for interaction >or= 0.24). The weight-mortality relations were somewhat attenuated when potential mediating and confounding factors were added to the multivariable models in both men with and men without a history of CHD., Conclusions: Avoidance of obesity and overweight in adult life in men with and without CHD may reduce their later risk of total and CHD mortality.

Study Objectives: There are contradictory perspectives on the importance of conventional coronary heart disease (CHD) risk factors in explaining population levels and social gradients in CHD. This study examined the contribution of conventional CHD risk factors (smoking, hypertension, dyslipidaemia, and diabetes) to explaining population levels and to absolute and relative social inequalities in CHD. This was investigated in an entire population and by creating a low risk sub-population with no smoking, dyslipidaemia, diabetes, and hypertension to simulate what would happen to relative and social inequalities in CHD if conventional risk factors were removed., Design, Setting, and Participants: Population based study of 2682 eastern Finnish men aged 42, 48, 54, 60 at baseline with 10.5 years average follow up of fatal (ICD9 codes 410-414) and non-fatal (MONICA criteria) CHD events., Main Results: In the whole population, 94.6% of events occurred among men exposed to at least one conventional risk factor, with a PAR of 68%. Adjustment for conventional risk factors reduced relative social inequality by 24%. However, in a low risk population free from conventional risk factors, absolute social inequality reduced by 72%., Conclusions: Conventional risk factors explain the majority of absolute social inequality in CHD because conventional risk factors explain the vast majority of CHD cases in the population. However, the role of conventional risk factors in explaining relative social inequality was modest. This apparent paradox may arise in populations where inequalities in conventional risk factors between social groups are low, relative to the high levels of conventional risk factors within every social group. If the concern is to reduce the overall population health burden of CHD and the disproportionate population health burden associated with the social inequalities in CHD, then reducing conventional risk factors will do the job.

Background: Coronary heart disease (CHD) is usually associated with "clustering" of risk factors. Insulin resistance may cause deleterious changes in several CHD risk factors and is of potential interest in the aetiology of clustered risk. We analyzed how glucose and insulin variables were associated with clustered risk., Methods: Participants were 489 young adults from Northern Ireland. Data were collected between October 1997 and October 1999. Nine risk factors were included in the clustered risk variable. Being "at risk" was defined as being in the upper quartile of risk for a particular risk factor. Subjects with clustered risk were defined as those displaying four or more risk factors. Blood glucose and insulin were measured in the fasting state and 2 h after ingestion of a 75 g glucose load., Results: Fasting insulin and the homeostasis model assessment insulin resistance score (HOMA) were strong, graded predictors of clustered risk. The odds ratio (OR) for having clustered risk was 10.8 (95% CI: 3.6-32.4) for the upper quartile of fasting insulin compared to the lowest quartile, and the corresponding OR for HOMA was 23.2 (95% CI: 5.3-101.6)., Conclusion: HOMA score predicts clustering of CHD risk factors. Fasting glucose alone did not predict clustering of risk factors, which may indicate that insulin resistance was compensated for by increased insulin secretion.

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

Context: Low adiponectin levels predict type 2 diabetes, and one prospective study in men reported its independent prediction of vascular events. Many observers thus already consider adiponectin to be a major part of the "common soil" underpinning diabetes and vascular disease., Objective: The objective of this study was to assess the association between adiponectin and incident coronary heart disease (CHD) risk in the British Women's Heart and Health Study., Design: This was a prospective (4 yr) case (n = 167) control (n = 334) study nested within the 4286 women in British Women's Heart and Health Study., Setting: The study was performed in a primary care setting., Participants: The study consisted of women (n = 4286) randomly selected from 23 British towns between 1999 and 2001, who were 60-79 yr of age at baseline., Main Outcome Measures: Association of adiponectin with CHD risk factors and incident CHD events were the main outcome measures., Results: Among both cases and controls, adiponectin positively correlated with age and high-density lipoprotein cholesterol and inversely correlated with waist to hip ratio, fasting insulin, fasting glucose, homeostasis model assessment of insulin resistance scores, C-reactive protein, and triglycerides. However, despite adequate power and these associations with CHD risk factors, adiponectin did not predict CHD events in unadjusted or adjusted analyses. The relative risk ratio for a doubling of adiponectin was 0.93 (95% confidence interval, 0.78, 1.11)., Conclusions: It is premature to consider adiponectin as a root for vascular disease in women despite its association with insulin resistance and diabetes. Additional prospective studies are required to determine whether there is a true sex difference in the effect of adiponectin on CHD.

Objective: To examine the associations of childhood and adult measurements of socioeconomic position with coronary heart disease (CHD) risk., Methods: Cross sectional and prospective analysis of a cohort of 4286 British women who were aged 60-79 years at baseline. Among these women there were 694 prevalent cases of CHD and 182 new incident cases among 13 217 person years of follow up of women who were free of CHD at baseline., Results: All measurements of socioeconomic position were associated with increased prevalent and incident CHD in simple age adjusted models. There was a cumulative effect, on prevalent and incident CHD, of socioeconomic position across the lifecourse. This effect was not fully explained by adult CHD risk factors. The adjusted odds ratio of prevalent CHD for each additional adverse (out of 10) lifecourse socioeconomic indicator was 1.11 (95% confidence interval: 1.06, 1.16). The magnitude of the effect of lifecourse socioeconomic position was the same in women who were lifelong non-smokers as in those who had been or were smokers., Conclusion: Adverse socioeconomic position across the lifecourse increases CHD risk cumulatively and this effect is not fully explained by adult risk factors. Specifically in this cohort of women cigarette smoking does not seem to explain the association between adverse lifecourse socioeconomic position and CHD risk.

Androgen level or androgen activity is implicated in several health outcomes, but its independent role remains controversial. This study investigated the association between history of acne in young adulthood, a marker of hormone activity, and cause-specific mortality in the Glasgow Alumni Cohort Study. Male students who attended Glasgow University between 1948 and 1968 and participated in voluntary health checks reported history of acne (n = 11,232). Vital status has been traced, and risk factors in adulthood are known for about 50% of the participants. Those with a history of acne were more often nonsmokers while university students and tended to be from a lower socioeconomic position. The two groups did not differ in other adolescent (height, body mass index, blood pressure, and number of siblings) or in most adult risk factors. Students who reported a history of acne had a lower risk of all-cause (hazard ratio = 0.89, 95% confidence interval (CI): 0.76, 1.04) and coronary heart disease (hazard ratio = 0.67, 95% CI: 0.48, 0.94) mortality but had some evidence of a higher risk of prostate cancer mortality (hazard ratio = 1.67, 95% CI: 0.79, 3.55). This study shows that androgen activity during adolescence may protect against coronary heart disease but confer a higher risk of prostate cancer mortality.

Background: Variation in the perception of bitter tastes has been associated with eating behavior, body composition, and cardiovascular disease. Recent observations have implicated 2 common haplotypes of TAS2R38 in the determination of bitter compound-tasting ability., Objective: The objectives of the study were to examine, in the British Women's Heart and Health Study cohort, any association between TAS2R38 haplotypes, coronary heart disease (CHD), CHD risk factors, and eating behavior and to examine whether the associations allow for estimation of the effects of variation in diet on the etiology of common disease., Design: We conducted a cross-sectional study of relations between TAS2R38 haplotypes and CHD, CHD risk factors, and eating behavior in 3383 women from 23 British towns., Results: Genotyping at P49A and V262A in TAS2R38 (rs713598 and rs1726866) allowed construction of all 4 possible haplotypes. The 2 most common haplotypes corresponded with previously identified haplotypes related to bitter compound-tasting ability. No substantial evidence of association was found between these haplotypes and CHD (odds ratio for taste-defining haplotypes: 0.97; 95% CI: 0.78, 1.2), body mass index (difference between means of taste-defining haplotypes: -0.084; 95% CI: -0.45, 0.29), or a series of physiologic and dietary characteristics. A marginally lower risk of diabetes was observed among those with the nontaster haplotype than among those with the taster haplotype (odds ratio: 0.69; 95% CI: 0.48, 1.00)., Conclusion: TAS2R38 status was not an important determinant of CHD, related risk factors, or eating behavior in the British Women's Heart and Health Study sample.

Study Objective: The aims of this study are to confirm the association between psychological distress and coronary heart disease (CHD) using an epidemiological community study with hospital admissions data and to examine if any association is explained by existing illness., Design: Prospective cohort study modelling the association between psychological distress, measured using the 30 item general health questionnaire (GHQ), and hospital admissions data for CHD (ICD 410-414), using proportional hazards modelling adjusted for sociodemographic, CHD risk factors, and angina, bronchitis, diabetes, ischaemia, and stroke., Setting: Two suburbs of Glasgow, Renfrew and Paisley, in Scotland., Participants: 6575 men and women aged 45-64 years from Paisley., Main Results: Five year CHD risk in distressed men compared with non-distressed men was 1.78 (95% confidence intervals (CI), 1.15 to 2.75) in age adjusted analysis, 1.78 (95% CI, 1.14 to 2.79) with sociodemographic and CHD risk factor adjustment, and 1.61 (95% CI 1.02 to 2.55) with additional adjustment for existing illness. Psychological distress was unrelated to five year CHD risk in women. In further analysis, compared with healthy, non-distressed men, distressed physically ill men had a greater risk of CHD than non-distressed physically ill men, a relative risk of 4.01 (95% CI 2.42 to 6.66) compared with 2.12 (95% CI 1.35 to 3.32)., Conclusion: The association of psychological distress with an increased risk of five year CHD risk in men could be a function of baseline physical illness but an effect independent of physical illness cannot be ruled out. Its presence among physically ill men greatly increases CHD risk.

Objectives: We sought to determine whether residential area deprivation, over and above the effect of life-course socioeconomic status or position (SEP), is associated with coronary heart disease., Methods: We conducted a cross-sectional analysis of 4286 women aged 60 to 79 years from 457 British electoral wards., Results: After adjustment for age and 10 indicators of individual life-course SEP, the odds of coronary heart disease was 27% greater among those living in wards with a deprivation score above the median compared with those living in a ward with a deprivation score equal to or below the median (odds ratio=1.27; 95% confidence interval=1.02, 1.57)., Conclusions: Adverse area-level socioeconomic characteristics, over and above individual life-course SEP, are associated with increased coronary heart disease.

Aims: To compare two proposed definitions of the metabolic syndrome and to determine the clinical importance of the syndrome with respect to its association with coronary heart disease (CHD)., Methods: Cross-sectional study of 3770 women aged 60-79 years randomly selected from 23 British towns., Results: The prevalence of the metabolic syndrome was high in this population and similar with both definitions: 28.2% (95% confidence interval 26.8, 29.7%) of the women had metabolic syndrome according to a modified version of the WHO definition, and 29.2% (27.7, 30.7%) had the ATP III-defined syndrome. There was reasonable agreement between the two definitions, with 79% of the participants being similarly classified by both definitions. The syndrome was associated with prevalent CHD, with the magnitude of the association with CHD being similar for both definitions. The odds ratio (95% confidence interval) for the age, smoking, physical activity, adult and childhood social class adjusted association of the WHO defined syndrome with prevalent CHD was 1.45 (1.19, 1.75) and for the ATP III-defined syndrome was 1.53 (1.27, 1.85). Insulin resistance alone, hypertension alone and dyslipidaemia alone were all associated with CHD, with the magnitudes of these associations being similar to those for the WHO and ATP III-defined syndrome with CHD., Conclusions: The prevalence of the metabolic syndrome is high in older British women and is associated with CHD. There is reasonable agreement between a modified version of the WHO definition and the ATP III definition of the syndrome, and both are similarly associated with CHD. Single components of the syndrome are associated with CHD to a similar magnitude as the syndrome., (Copyright 2004 Diabetes UK)

Objective: To assess the associations between components of adult height and coronary heart disease (CHD) in postmenopausal women., Methods: Cross sectional analysis of 4286 women randomly selected from 23 British towns. The association of components of adult height with prevalent CHD (n = 694) were assessed., Results: Shorter stature, shorter leg length, and trunk length were all associated with CHD in age adjusted analyses. The association between trunk length and CHD was attenuated to the null with adjustment for smoking. The leg length-CHD association was independent of smoking, socioeconomic position in childhood and adulthood, birth weight, and other potential confounders. Insulin resistance did not appear to be an important mediating factor in the association between leg length and CHD. After full adjustment for all potential confounding factors the odds ratio (95% confidence interval) of CHD for a 1 SD (4.3 cm) increase in leg length was 0.84 (0.77 to 0.93) and the odds ratio for a 1 SD (0.05) increase in the leg to trunk ratio was 0.85 (0.79 to 0.95)., Conclusions: The specific association between leg length and CHD suggests that early life environmental exposures that influence skeletal growth also influence CHD risk in later life.

Objective: To assess the association of mean outdoor temperature around the time of birth with insulin resistance and coronary heart disease in later life., Design: Cross sectional study., Setting: 23 British towns., Participants: 4286 women aged 60-79 years., Main Outcome Measures: Coronary heart disease and insulin resistance., Results: Coronary heart disease prevalence was greatest among women born during the coldest months: the age adjusted odds ratio comparing women born in the coldest quarter of monthly outdoor birth temperatures with the remaining three quarters was 1.24 (95% confidence interval (CI) 1.03 to 1.50). Cold outdoor temperature at birth was also associated with increased insulin resistance, increased triglyceride concentrations, and poorer lung function. The link between cold outdoor temperature at birth and coronary heart disease was only partly explained by known coronary disease risk factors: fully adjusted (for all measured potential explanatory and confounding factors) odds ratio 1.19 (95% CI 0.95 to 1.48). The association between cold temperature at birth and coronary heart disease was most pronounced among those whose fathers were either unemployed or in manual social classes when the participants were children, and was non-existent in those from non-manual social classes in childhood., Conclusions: Cold outdoor temperature at birth is associated with increased coronary heart disease, insulin resistance, dyslipidaemia, and poor lung function. Further research is needed to determine whether this finding reflects events occurring late in the third trimester of intrauterine growth or early in the postnatal period.

Objectives: (1) To assess the association between birth weight and coronary heart disease (CHD) risk in a cohort of post-menopausal women, (2) to determine the combined effects of birth weight and adult body mass index on CHD, (3) to assess the role of insulin resistance as a mediating factor in the associations., Design: Cross sectional survey., Setting: 23 British towns., Participants: 1394 women aged 60-79 years., Main Outcome Measures: coronary heart disease (n = 199 cases)., Results: Birth weight was inversely associated with CHD: age and survivor status of participant's mother adjusted odds ratio (95% confidence intervals) per 1 standard deviation (0.80 kg) increase in birth weight was 0.84 (0.72 to 0.97). This association strengthened to 0.80 (0.68 to 0.93) with further adjustment for adult body mass index, but there was no evidence of an interaction between birth weight and adult body mass index (p = 0.61). The association was not confounded by childhood or adulthood socioeconomic position or by adult smoking status of the participant. Adjustment for components of the insulin resistance syndrome attenuated the association to 0.87 (0.72 to 1.03)., Conclusions: Intrauterine exposures that affect fetal growth also affect future adult CHD risk. The inverse association between birth weight and CHD may in part be mediated via insulin resistance.

Background: Psychological interventions can form part of comprehensive cardiac rehabilitation programmes (CCR). These interventions may include stress management interventions, which aim to reduce stress, either as an end in itself or to reduce risk for further cardiac events in patients with heart disease., Objectives: To determine the effectiveness of psychological interventions, in particular stress management interventions, on mortality and morbidity, psychological measures, quality of life, and modifiable cardiac risk factors, in patients with coronary heart disease (CHD)., Search Strategy: We searched CCTR to December 2001 (Issue 4, 2001), MEDLINE 1999 to December 2001 and EMBASE 1998 to the end of 2001, PsychINFO and CINAHL to December 2001. In addition, searches of reference lists of papers were made and expert advice was sought., Selection Criteria: RCTs of non-pharmacological psychological interventions, administered by trained staff, either single modality interventions or a part of CCR with minimum follow up of 6 months. Adults of all ages with CHD (prior myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, angina pectoris or coronary artery disease defined by angiography). Stress management (SM) trials were identified and reported in combination with other psychological interventions and separately., Data Collection and Analysis: Studies were selected, and data were abstracted, independently by two reviewers. Authors were contacted where possible to obtain missing information., Main Results: Thirty six trials with 12,841 patients were included. Of these, 18 (5242 patients) were SM trials. Quality of many trials was poor with the majority not reporting adequate concealment of allocation, and only 6 blinded outcome assessors. Combining the results of all trials showed no strong evidence of effect on total or cardiac mortality, or revascularisation. There was a reduction in the number of non-fatal reinfarctions in the intervention group (OR 0.78 (0.67, 0.90), but the two largest trials (with 4809 patients randomized) were null for this outcome, and there was statistical evidence of publication bias. Similar results were seen for the SM subgroup of trials. Provision of any psychological intervention or SM intervention caused small reductions in anxiety and depression. Few trials reported modifiable cardiac risk factors or quality of life., Reviewers' Conclusions: Overall psychological interventions showed no evidence of effect on total or cardiac mortality, but did show small reductions in anxiety and depression in patients with CHD. Similar results were seen for SM interventions when considered separately. However, the poor quality of trials, considerable heterogeneity observed between trials and evidence of significant publication bias make the pooled finding of a reduction in non-fatal myocardial infarction insecure.