Dataset Information

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

ABSTRACT: 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.

SUBMITTER: IL6R Genetics Consortium Emerging Risk Factors Collaboration

PROVIDER: S-EPMC3316940 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

Sarwar Nadeem N Butterworth Adam S AS Freitag Daniel F DF Gregson John J Willeit Peter P Gorman Donal N DN Gao Pei P Saleheen Danish D Rendon Augusto A Nelson Christopher P CP Braund Peter S PS Hall Alistair S AS Chasman Daniel I DI Tybjærg-Hansen Anne A Chambers John C JC Benjamin Emelia J EJ Franks Paul W PW Clarke Robert R Wilde Arthur A M AA Trip Mieke D MD Steri Maristella M Witteman Jacqueline C M JC Qi Lu L van der Schoot C Ellen CE de Faire Ulf U Erdmann Jeanette J Stringham Heather M HM Koenig Wolfgang W Rader Daniel J DJ Melzer David D Reich David D Psaty Bruce M BM Kleber Marcus E ME Panagiotakos Demosthenes B DB Willeit Johann J Wennberg Patrik P Woodward Mark M Adamovic Svetlana S Rimm Eric B EB Meade Tom W TW Gillum Richard F RF Shaffer Jonathan A JA Hofman Albert A Onat Altan A Sundström Johan J Wassertheil-Smoller Sylvia S Mellström Dan D Gallacher John J Cushman Mary M Tracy Russell P RP Kauhanen Jussi J Karlsson Magnus M Salonen Jukka T JT Wilhelmsen Lars L Amouyel Philippe P Cantin Bernard B Best Lyle G LG Ben-Shlomo Yoav Y Manson JoAnn E JE Davey-Smith George G de Bakker Paul I W PI O'Donnell Christopher J CJ Wilson James F JF Wilson Anthony G AG Assimes Themistocles L TL Jansson John-Olov JO Ohlsson Claes C Tivesten Åsa Å Ljunggren Östen Ö Reilly Muredach P MP Hamsten Anders A Ingelsson Erik E Cambien Francois F Hung Joseph J Thomas G Neil GN Boehnke Michael M Schunkert Heribert H Asselbergs Folkert W FW Kastelein John J P JJ Gudnason Vilmundur V Salomaa Veikko V Harris Tamara B TB Kooner Jaspal S JS Allin Kristine H KH Nordestgaard Børge G BG Hopewell Jemma C JC Goodall Alison H AH Ridker Paul M PM Hólm Hilma H Watkins Hugh H Ouwehand Willem H WH Samani Nilesh J NJ Kaptoge Stephen S Di Angelantonio Emanuele E Harari Olivier O Danesh John J

Lancet (London, England) 20120314 9822

<h4>Background</h4>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.<h4>Methods</h4>In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conven ...[more]

PMID: 22421339

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Project description:BackgroundWhether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.MethodsWe assessed the -1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20,842 patients with coronary heart disease, 35,206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12,785 incident cases of coronary heart disease during 2.79 million person-years at risk). We analysed -1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.FindingsThe minor allele frequency of -1131T>C was 8% (95% CI 7-9). -1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6-4.6]; 0.053 mmol/L [0.039-0.068]), lower apolipoprotein AI (1.3% [0.3-2.3]; 0.023 g/L [0.005-0.041]), and higher apolipoprotein B (3.2% [1.3-5.1]; 0.027 g/L [0.011-0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9-18.7), or 0.25 mmol/L (0.20-0.29), higher (p=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-7)) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08-1.12) per 16% higher triglyceride concentration recorded in prospective studies. -1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects of triglyceride.InterpretationThese data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.FundingBritish Heart Foundation, UK Medical Research Council, Novartis.

Project description:BACKGROUND: Depression and coronary heart disease (CHD) are frequently comorbid and portend higher morbidity, mortality and poorer quality of life. Prior systematic reviews of depression treatment randomized controlled trials (RCTs) in the population with CHD have not assessed the efficacy of collaborative care. This systematic review aims to bring together the contemporary research on the effectiveness of collaborative care interventions for depression in comorbid CHD populations. METHODS/DESIGN: Electronic databases (Cochrane Central Register of Controlled Trials MEDLINE, EMBASE, PsycINFO and CINAHL) will be searched using a sensitive search strategy exploding the topics CHD, depression and RCT. Full text inspection and bibliography searching will be conducted, and authors of included studies will be contacted to identify unpublished studies. Eligibility criteria are: population, depression comorbid with CHD; intervention, RCT of collaborative care defined as a coordinated model of care involving multidisciplinary health care providers, including: (a) primary physician and at least one other health professional (e.g. nurse, psychiatrist, psychologist), (b) a structured patient management plan that delivers either pharmacological or non-pharmacological intervention, (c) scheduled patient follow-up and (d) enhanced inter-professional communication between the multiprofessional team; comparison, either usual care, enhanced usual care, wait-list control group or no further treatment; and outcome, major adverse cardiac events (MACE), standardized measure of depression, anxiety, quality of life, cost-effectiveness. Screening, data extraction and risk of bias assessment will be undertaken by two reviewers with disagreements resolved through discussion. Meta-analytic methods will be used to synthesize the data collected relating to the outcomes. DISCUSSION: This review will evaluate the effectiveness and cost-effectiveness of collaborative care for depression in populations primarily with CHD. The results will facilitate integration of evidence-based practice for this precarious population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014013653.

Project description:BACKGROUND:Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies. METHODS:We used individual records from 13 European cohort studies (1985-2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. FINDINGS:30,214 (15%) of 197,473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10-1·37). This effect estimate was higher in published (1·43, 1·15-1·77) than unpublished (1·16, 1·02-1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15-1·48) and 5 years (1·30, 1·13-1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%. INTERPRETATION:Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking. FUNDING:Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.

Project description:BackgroundDepression, as an independent risk factor, can lead to a substantially increased risk of coronary heart disease (CHD). The overall body of evidence involving depression and CHD is not consistent. Therefore, we performed an update meta-analysis to evaluate the association between depression and the risk of patients with CHD.MethodsStudies were identified through a comprehensive literature search of the PubMed, Embase, and the Cochrane Library database from its inception to 28 September 2021 for titles/abstracts with restricted to English language articles. The literature was screened according to the inclusion and exclusion criteria. Along with data extraction, we evaluated the quality of eligible studies using the Newcastle-Ottawa Scale (NOS). The primary outcome was fatal or non-fatal CHD. We calculated relative risk (RR) with 95% confidence intervals (CIs) using a random-effects models. The protocol was registered in the PROSPERO registration (registration number CRD42021271259).ResultsFrom 9,151 records, we included 26 prospective cohort studies published from 1998 to 2018, consisting of 402,597 patients. Either in depression-exposured group or non-depression-exposured group, the mean age of all participants ranged from 18 to 99 years. Moreover, the NOS scores of these studies are eventually indicated that the quality of these eligible studies was reliable. In general, the pooled results showed that patients with depression had a higher risk of CHD compared to patients without depression (RR = 1.21, 95% CI: 1.14-1.29). Additionally, the funnel plot appeared to be asymmetry, indicating there existing publication bias for the pooled results between depression and CHD. A sensitivity analysis was used to assess the stability of the relationship between depression and CHD that indicating the results robust (RR = 1.15, 95% CI: 1.09-1.21).ConclusionDepression may increase risk of CHD. Future studies on the share pathogenic mechanisms of both depression and CHD may develop novel therapies.

Project description:BackgroundA high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.MethodsApplying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis.FindingsIn 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)).InterpretationOn the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.FundingUK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.

Dataset Information

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

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Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

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