Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review
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BACKGROUND: The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. METHODS AND FINDINGS: Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28-0.53, over 4 y, and 0.35, 95% CI 0.23-0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29-1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45-3.15) with long-term average ("usual") IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42-1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45-4.56] per 2 SD increase in usual [long-term average] IL-6 levels). CONCLUSIONS: Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CHD.
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IL-6 and CRP are key indicators of disease risk in middle-age and older adulthood as they are prospectively associated with coronary heart disease, diabetes, disability, and all-cause mortality.
“Biomarkers of systemic inflammation, including interleukin-6 (IL-6) and C-reactive protein (CRP) are key indicators of disease risk in middle-age and older adulthood as they are prospectively associated with coronary heart disease (17,18) as well as diabetes (19), disability (20), and all-cause mortality (21).”
From Socioeconomic Status Interacts with Conscientiousness and Neuroticism to Predict Circulating Concentrations of Inflammatory Markers (2017) · cites this paper as [18]
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“Biomarkers of systemic inflammation, including interleukin-6 (IL-6) and C-reactive protein (CRP), are key indicators of disease risk in middle age and older adulthood as they are prospectively associated with coronary heart disease [17, 18] as well as diabetes [19], disability [20], and all-cause mortality [21].”
BackgroundReview on cardiovascular risk prediction
Ruwanpathirana, T., Owen, A., & Reid, C. M. (2015) · Cardiovascular Therapeutics · doi:10.1111/1755-5922.12110 · Cited by 31 · see citing works
Cardiovascular biomarkers in clinical studies of type 2 diabetes
Baldassarre, M. P. A., Andersen, A., Consoli, A., Knop, F. K., & Vilsbøll, T. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13247 · Cited by 22 · see citing works
- Authors
- Danesh, J., Kaptoge, S., Mann, A. G., Sarwar, N., Wood, A., Angleman, S. B., Wensley, F., Higgins, J. P. T., Lennon, L., Eiriksdottir, G., Rumley, A., Whincup, P. H., Lowe, G. D. O., & Gudnason, V.
- Affiliations
- University of Cambridge (GB)
- MRC Biostatistics Unit (GB)
- The Royal Free Hospital (GB)
- University of Glasgow (GB)
- St George's, University of London (GB)
- University of Iceland (IS)
- Corresponding author
- Danesh, John
- ORCID
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-04-08
- Volume
- 5
- Issue
- 4
- Pages
- e78
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC2288623
- OpenAlex
- W2164189703
- Cited by
- 676
- References
- 53
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 19 · 2023: 16 · 2022: 23 · 2021: 43 · 2020: 36 · 2019: 33 · 2018: 35 · 2017: 40 · 2016: 43 · 2015: 41 · 2014: 52 · 2013: 69 · 2012: 50
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- GlaxoSmithKline
- British Heart Foundation
- National Institutes of Health
- National Institute on Aging
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- interleukin-6, coronary artery disease, myocardial infarction, coronary death, inflammation, cytokines, within-person variability, regression dilution, C-reactive protein, cardiovascular risk factors, serial biomarker measurement, prospective cohort
- MeSH terms
- Coronary Disease, Female, Humans, Inflammation, Male, Middle Aged, Prospective Studies, Risk Factors, Cohort Studies, Interleukin-6
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