The DOI matches its Crossref record; 46 of the 47 references it cites were found in a registry or an index.
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“genetic evidence suggests that IL-6 may be causal for atherosclerotic cardiovascular disease, 24,25”
From Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide (2026) · cites this paper as [24]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Measuring inconsistency in meta-analyses
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003) · BMJ · doi:10.1136/bmj.327.7414.557 · Cited by 63,139
Progress and challenges in translating the biology of atherosclerosis
Libby, P., Ridker, P. M., & Hansson, G. K. (2011) · Nature · doi:10.1038/nature10146 · Cited by 4,010
Scott, D. L., Wolfe, F., & Huizinga, T. W. J. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60826-4 · Cited by 3,263
Ridker, P. M., Rifai, N., Stampfer, M. J., & Hennekens, C. H. (2000) · Circulation · doi:10.1161/01.cir.101.15.1767 · Cited by 2,429
The immune system in atherosclerosis
Hansson, G. K., & Hermansson, A. (2011) · Nature Immunology · doi:10.1038/ni.2001 · Cited by 2,389
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
Cardiogenics, Schunkert, H., the CARDIoGRAM Consortium, König, I. R., Kathiresan, S., Reilly, M. P., Assimes, T. L., Holm, H., Preuss, M., Stewart, A. F. R., et al. (2011) · Nature Genetics · doi:10.1038/ng.784 · Cited by 1,866
Plasma Fibrinogen Level and the Risk of Major Cardiovascular Diseases and Nonvascular Mortality
Danesh, J., Lewington, S., Thompson, S. G., Lowe, G. D. O., Collins, R., Kostis, J. B., Wilson, A. C., Folsom, A. R., Wu, K., Benderly, M., et al. (2005) · JAMA · doi:10.1001/jama.294.14.1799 · Cited by 1,162
Population genomics of human gene expression
Stranger, B. E., Nica, A. C., Forrest, M. S., Dimas, A. S., Bird, C., Beazley, C., Ingle, C., Dunning, M., Flicek, P., Koller, D., et al. (2007) · Nature Genetics · doi:10.1038/ng2142 · Cited by 1,153
Genomics, type 2 diabetes, and obesity
McCarthy, M. I. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0906948 · Cited by 938
Mapping the Genetic Architecture of Gene Expression in Human Liver
Schadt, E. E., Molony, C. M., Chudin, E., Hao, K., Yang, X., Lum, P. Y., Kasarskis, A., Zhang, B., Wang, S. S.-M., Suver, C., et al. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060107 · Cited by 918
Ridker, P. M., Thuren, T., Zalewski, A., & Libby, P. (2011) · American Heart Journal · doi:10.1016/j.ahj.2011.06.012 · Cited by 799
Common Regulatory Variation Impacts Gene Expression in a Cell Type–Dependent Manner
Dimas, A. S., Deutsch, S., Stranger, B. E., Montgomery, S. B., Borel, C., Attar, H., Ingle, C., Beazley, C., Arcelus, M. G., Sekowska, M., et al. (2009) · Science · doi:10.1126/science.1174148 · Cited by 740
Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies
(2010) · The Lancet · doi:10.1016/s0140-6736(10)60545-4 · Cited by 716
Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010
Fürst, D. E., Keystone, E. C., Braun, J., Breedveld, F. C., Burmester, G. R., Benedetti, F. D., Dorner, T. E., Emery, P., Fleischmann, R., Gibofsky, A., et al. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.146852 · Cited by 688
Danesh, J., Kaptoge, S., Mann, A. G., Sarwar, N., Wood, A., Angleman, S. B., Wensley, F., Higgins, J. P. T., Lennon, L., Eiriksdottir, G., et al. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050078 · Cited by 676
C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) (2011) · BMJ · doi:10.1136/bmj.d548 · Cited by 642
Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility
Zeller, T., Wild, P. S., Szymczak, S., Rotival, M., Schillert, A., Castagné, R., Maouche, S., Germain, M., Lackner, K. J., Rossmann, H., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010693 · Cited by 595
Reilly, M. P., Li, M., He, J., Ferguson, J. F., Stylianou, I. M., Mehta, N. N., Burnett, M. S., Devaney, J. M., Knouff, C. W., Thompson, J. R., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(10)61996-4 · Cited by 547
Dehghan, A., Dupuis, J., Barbalić, M., Bis, J. C., Eiríksdóttir, G., Lu, C., Pellikka, N., Wallaschofski, H., Kettunen, J., Henneman, P., et al. (2011) · Circulation · doi:10.1161/circulationaha.110.948570 · Cited by 507
A genome-wide association study identifies protein quantitative trait loci (pQTLs)
Melzer, D., Perry, J. R. B., Hernandez, D., Corsi, A.-M., Stevens, K., Rafferty, I., Lauretani, F., Murray, A., Gibbs, J. R., Paolisso, G., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000072 · Cited by 480
The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study
Nica, A. C., Parts, L., Glass, D., Nisbet, J. P., Barrett, A., Sekowska, M., Travers, M. E., Potter, S., Grundberg, E., Small, K. S., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002003 · Cited by 396
Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
Ferreira, M. A., Matheson, M. C., Duffy, D. L., Marks, G. B., Hui, J., Le Souëf, P., Danoy, P., Baltic, S., Nyholt, D. R., Jenkins, M., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60874-x · Cited by 381
Ridker, P. M., Paré, G., Parker, A. N., Zee, R. Y. L., Danik, J. S., Buring, J. E., Kwiatkowski, D. J., Cook, N. R., Miletich, J. P., & Chasman, D. I. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.03.015 · Cited by 341
How much is too much? Interleukin-6 and its signalling in atherosclerosis
Schuett, H., Luchtefeld, M., Grothusen, C., Grote, K., & Schieffer, B. (2009) · Thrombosis and Haemostasis · doi:10.1160/th09-05-0297 · Cited by 299
Choy, E., & Sattar, N. A. (2009) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.101964 · Cited by 296
The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site.
Müllberg, J., OBERTHÜR, W., Lottspeich, F., Mehl, E., Dittrich, E., Graeve, L., Heinrich, P. C., & Rose‐John, S. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.10.4958 · Cited by 269
Ridker, P. M. (2009) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2009.03404.x · Cited by 269
The meta-analysis of genome-wide association studies
Thompson, J. R., Attia, J., & Minelli, C. (2011) · Briefings in Bioinformatics · doi:10.1093/bib/bbr020 · Cited by 251
Schmitt, C., Kuhn, B., Zhang, X.-P., Kivitz, A., & Grange, S. (2011) · Clinical pharmacology and therapy · doi:10.1038/clpt.2011.35 · Cited by 249
Transsignaling of Interleukin-6 Crucially Contributes to Atherosclerosis in Mice
Schuett, H., Oestreich, R., Waetzig, G. H., Annema, W., Luchtefeld, M., Hillmer, A., Bavendiek, U., von Felden, J., Divchev, D., Kempf, T., et al. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.229435 · Cited by 243
Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
The IBC 50K CAD Consortium (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002260 · Cited by 237
Admixture Mapping of an Allele Affecting Interleukin 6 Soluble Receptor and Interleukin 6 Levels
Reich, D., Patterson, N. J., Ramesh, V., Jager, P. L. D., McDonald, G. J., Tandon, A., Choy, E., Hu, D., Tamraz, B., Pawlikowska, L., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/513206 · Cited by 169
Linsel‐Nitschke, P., Götz, A., Erdmann, J., Brænne, I., Braund, P. S., Hengstenberg, C., Stark, K. J., Fischer, M., Schreiber, S., Mokhtari, N. E. E., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002986 · Cited by 168
Protogerou, A. D., Zampeli, E., Fragiadaki, K., Stamatelopoulos, K., Papamichael, C. M., & Sfikakis, P. P. (2011) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2011.09.015 · Cited by 145
Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization’
Keavney, B. D., Danesh, J., Parish, S., Palmer, A., Clark, S., Youngman, L. D., Délepine, M., Lathrop, M. G., Peto, R., & Collins, R. (2006) · International Journal of Epidemiology · doi:10.1093/ije/dyl114 · Cited by 142
Cardiovascular Biology of Interleukin-6
Abeywardena, M. Y., Leifert, W. R., Warnes, K., Varghese, J. N., & Head, R. J. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788186290 · Cited by 128
Danik, J. S., Paré, G., Chasman, D. I., Zee, R. Y. L., Kwiatkowski, D. J., Parker, A. N., Miletich, J. P., & Ridker, P. M. (2009) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.108.825273 · Cited by 86
Eleftherohorinou, H., Hoggart, C. J., Wright, V., Levin, M., & Coin, L. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr248 · Cited by 69
Stephens, O., Zhang, Q., Qu, P., Zhou, Y., Chavan, S. S., Tian, E., Williams, D. R., Epstein, J., Barlogie, B., & Shaughnessy, J. D. (2011) · Blood · doi:10.1182/blood-2011-07-367052 · Cited by 65
Atherogenic lipid profiles and its management in patients with rheumatoid arthritis.
Nurmohamed, M. T. (2007) · PubMed · Cited by 56
Clinical safety of tocilizumab in rheumatoid arthritis
Bannwarth, B., & Richez, C. (2011) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2011.537256 · Cited by 50
Wassel, C. L., Lange, L. A., Keating, B. J., Taylor, K. C., Johnson, A. D., Palmer, C. D., Ho, L. A., Smith, N. L., Lange, E. M., Li, Y., et al. (2010) · Blood · doi:10.1182/blood-2010-06-289546 · Cited by 40
Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease
Elliott, P. (2009) · JAMA · doi:10.1001/jama.2009.954 · Cited by 35
A gain of function polymorphism in the interleukin 6 receptor influences RA susceptibility
Μαρίνου, Ι., Walters, K., Winfield, J., Bax, D. E., & Wilson, A. G. (2009) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.100644 · Cited by 25
Research works printed but not linked: 2
- Lamas, 2011, Mechanisms underlying the generation of soluble IL-6 soluble receptor (sIL-6R) in rheumatoid arthritis: mRNA alternative splicing and proteolytic cleavage as independent contributors, Arthritis Rheum, 63, 383
- Genovese, 2009, Analysis of low-density lipoprotein and adverse events in rheumatoid arthritis patients treated with tocilizumab plus statins: data from five phase III clinical trials, Rheumatology (Oxford), 48, I81
Cited by
Sorted by citations
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707914 · Cited by 9,482
Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Ferrucci, L., & Fabbri, E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0064-2 · Cited by 3,690
IL-6 as a keystone cytokine in health and disease
Hunter, C. A., & Jones, S. A. (2015) · Nature Immunology · doi:10.1038/ni.3153 · Cited by 2,511
Burgess, S., Bowden, J., Fall, T., Ingelsson, E., & Thompson, S. G. (2017) · Epidemiology · doi:10.1097/ede.0000000000000559 · Cited by 2,017
Metadata
- Authors
- ‡
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- ‡
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 379
- Issue
- 9822
- Pages
- 1205-1213
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3316940
- OpenAlex
- W2139957955
- Cited by
- 823
- References
- 47
- Citations by year
- 2026: 48 · 2025: 46 · 2024: 63 · 2023: 46 · 2022: 50 · 2021: 69 · 2020: 73 · 2019: 57 · 2018: 61 · 2017: 60 · 2016: 58 · 2015: 48 · 2014: 72 · 2013: 48 · 2012: 23
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- British Heart Foundation (RG/08/014)
- Bupa Foundation
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- IL-6 receptor, coronary artery disease, rs2228145, genetic association, inflammation, C-reactive protein, fibrinogen, interleukin-6, chronic inflammation, cardiovascular risk factors, monocytes, gene expression
- MeSH terms
- Coronary Disease, Gene Frequency, Humans, Risk Factors, Genetic Variation, Signal Transduction, Causality, Inflammation Mediators, Receptors, Interleukin-6
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
