Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review

By John Danesh, S. Kaptoge, A. Mann, N. Sarwar, Angela M. Wood, Sara B. Angleman, F. Wensley, Julian P. T. Higgins, L. Lennon, G. Eiriksdottir and 4 more. PLoS Medicine, 2008

710 citations recorded by the source corpus.

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.

Subfields: Cardiology and Cardiovascular Medicine, Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/46f22b85e3a422f33737c7426b66cb998b4254e9

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In Epidemiology

1. G. Lewis
2. Peter B. Jones
3. L. Baxter
4. G. Khandaker
5. E. Osimo

In Immunology

1. J. Snyder-Cappione
2. Anna C. Belkina
3. Frank O. Nestle
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Citations in the corpus

• Markers of Inflammation, Coagulation and Renal Function Are Elevated in Adults with HIV Infection (2010, background): “Each of the biomarkers has been associated with cardiovascular disease in the general population [17–24], and 3 of the biomarkers (hsCRP, IL-6, and D-dimer) have recently been associated with all-cause mortality in the SMART study [3].”
• Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. (2014, neutral): “Nat Rev Drug Discov 2010 Sep;9(9):703-718.”
• Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients (2008, neutral): “How could elevated levels of IL-6 be linked with excess risk of CVD? Elevated levels of IL-6 are recognized to be associated with an increased risk of CVD [16,17].”
• Obesity and inflammation: the linking mechanism and the complications (2016, background): “Circulating inflammatory mediators including IL-6 have been hypothesized to play a substantial role in the development and alteration of several diseases [30–32].”
• Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels (2019, background): “…2003), because CVD is associated with circulating IL-6 and CRP levels (Pradhan et al., 2002; Danesh 1966 Emanuele Felice Osimo et al. et al., 2004; Danesh et al., 2008) and with genetic variants regulating levels/activity of IL-6 (IL6R Genetics Consortium Emerging Risk Factors Collaboration,…”
• Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging (2018, methodology): “Mortality and age-associated co-morbidities among HIV+ individuals track with plasma inflammatory and coagulation markers, such as C-reactive protein (CRP), IL-6, D-dimer, and fibrinogen [9-14], similar to the general population [15-21].”
• Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. (2010, background): “, 2007) and also appear to predict an elevated risk of vascular events, at least as strongly as C-reactive protein (CRP) (Danesh et al., 2008).”