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.
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Genetic evidence suggests that IL-6 may be causal for atherosclerotic cardiovascular disease.
“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]
The Discussion reports genetic and biomarker evidence consistent with a causal association between IL6R-related pathways and coronary heart disease. The claim broadens that finding from IL6R pathways to IL-6 itself and from coronary heart disease to atherosclerotic cardiovascular disease generally; the Discussion identifies non-coronary outcomes as a subject for future study. (LLM, conf=0.86)
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- 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 › Epidemiology › 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
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