Dataset Information

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

ABSTRACT:

Background

A 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.

Methods

Applying 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.

Findings

In 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)).

Interpretation

On 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.

Funding

UK 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.

SUBMITTER: Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium

PROVIDER: S-EPMC3316968 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

Swerdlow Daniel I DI Holmes Michael V MV Kuchenbaecker Karoline B KB Engmann Jorgen E L JE Shah Tina T Sofat Reecha R Sofat Reecha R Guo Yiran Y Chung Christina C Peasey Anne A Pfister Roman R Mooijaart Simon P SP Ireland Helen A HA Leusink Maarten M Langenberg Claudia C Li Ka Wah KW Palmen Jutta J Howard Philip P Cooper Jackie A JA Drenos Fotios F Hardy John J Nalls Michael A MA Li Yun Rose YR Lowe Gordon G Stewart Marlene M Bielinski Suzette J SJ Peto Julian J Timpson Nicholas J NJ Gallacher John J Dunlop Malcolm M Houlston Richard R Tomlinson Ian I Tzoulaki Ioanna I Luan Jian'an J Boer Jolanda M A JM Forouhi Nita G NG Onland-Moret N Charlotte NC van der Schouw Yvonne T YT Schnabel Renate B RB Hubacek Jaroslav A JA Kubinova Ruzena R Baceviciene Migle M Tamosiunas Abdonas A Pajak Andrzej A Topor-Madry Roman R Malyutina Sofia S Baldassarre Damiano D Sennblad Bengt B Tremoli Elena E de Faire Ulf U Ferrucci Luigi L Bandenelli Stefania S Tanaka Toshiko T Meschia James F JF Singleton Andrew A Navis Gerjan G Mateo Leach Irene I Bakker Stephan J L SJ Gansevoort Ron T RT Ford Ian I Epstein Stephen E SE Burnett Mary Susan MS Devaney Joe M JM Jukema J Wouter JW Westendorp Rudi G J RG Jan de Borst Gert G van der Graaf Yolanda Y de Jong Pim A PA Mailand-van der Zee Anke-Hilse AH Klungel Olaf H OH de Boer Anthonius A Doevendans Pieter A PA Stephens Jeffrey W JW Eaton Charles B CB Robinson Jennifer G JG Manson JoAnn E JE Fowkes F Gerry FG Frayling Timonthy M TM Price Jackie F JF Whincup Peter H PH Morris Richard W RW Lawlor Debbie A DA Smith George Davey GD Ben-Shlomo Yoav Y Redline Susan S Lange Leslie A LA Kumari Meena M Wareham Nick J NJ Verschuren W M Monique WM Benjamin Emelia J EJ Whittaker John C JC Hamsten Anders A Dudbridge Frank F Delaney J A Chris JA Wong Andrew A Kuh Diana D Hardy Rebecca R Castillo Berta Almoguera BA Connolly John J JJ van der Harst Pim P Brunner Eric J EJ Marmot Michael G MG Wassel Christina L CL Humphries Steve E SE Humphries Steve E SE Talmud Philippa J PJ Kivimaki Mika M Asselbergs Folkert W FW Voevoda Mikhail M Bobak Martin M Pikhart Hynek H Wilson James G JG Hakonarson Hakon H Reiner Alex P AP Keating Brendan J BJ Sattar Naveed N Hingorani Aroon D AD Casas Juan Pablo JP

Lancet (London, England) 20120314 9822

<h4>Background</h4>A 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.<h4>Methods</h4>Applying the mendelian randomisation principle, we used single nucleotide polymorphisms ( ...[more]

PMID: 22421340

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Project description:Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3×10-8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits.

Project description:BackgroundIncreased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.MethodsWe first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.FindingsIn the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate.InterpretationConventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.FundingUK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.

Project description:BackgroundTo investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation.MethodsWe created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants).FindingsFor each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p = 9.3 × 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1.7%; p = 3.5 × 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p = 7.7 × 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 × 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p = 3.9 × 10(-10)). Per-allele odds ratios were 0.97 (0.95-0.99; p = 9.9 × 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p = 0.47) for type 2 diabetes, 1.00 (0.98-1.02; p = 0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p = 1.8 × 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk.InterpretationHuman genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations.

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Dataset Information

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

Background

Methods

Findings

Interpretation

Funding

Publications

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

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