JD, PHW, and VG conceived and designed the current work. SK and FW analysed the data. JD and SK drafted the paper. JD, SK, NS, AW, SBA, FW, JPTH, GE, AR, PHW, GDOL, and VG contributed to the writing of the paper. SK, AGM, NS, FW, and JPTH conducted the systematic review. LL collected the follow-up data in the BRHS. AR and GDOL supervised IL-6 assays.
The authors have declared that no competing interests exist.
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.
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).
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.
John Danesh and colleagues show that long-term IL-6 levels are associated with coronary heart disease risk, thus highlighting the potential relevance of IL-6−mediated pathways to coronary heart disease.
Coronary heart disease (CHD), the leading cause of death among adults in developed countries, kills one person in the US every minute. With age, “atherosclerotic plaques”—deposits of fats, calcium, and various cellular waste products—coat the walls of arteries, causing them to narrow and harden, interrupting blood flow through the body. When this occurs in the coronary arteries, which nourish the heart muscle, the end result is CHD. If a plaque breaks off the artery wall, it can get trapped in the arteries and completely stop the blood flow, causing death of the heart muscle. The technical term for this is “myocardial infarction” (MI), although it is more commonly known as a heart attack. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), being overweight, and being physically inactive all increase the risk of developing CHD, as do some inherited factors. Treatments for CHD include lifestyle changes (for example, losing weight and exercising regularly) and medications that lower blood pressure and blood cholesterol. In the worst cases, the narrowed artery can be widened using a device called a stent or surgically bypassed.
Atherosclerosis might, at least partly, be an inflammatory condition. Inflammation—an immune response to injury characterized by swelling and redness—involves the production of proteins called “cytokines,” which attract cells of the immune system to the site of injury. In atherosclerosis, damage to the artery walls seems to trigger inflammation, which helps the atherosclerotic plaques grow. Because of the potential involvement of inflammation in atherosclerosis, increased levels of circulating cytokines might be associated with an increased risk of CHD. If they are, cytokines might provide a new therapeutic target for the treatment of CHD. In this study, the researchers have asked whether prolonged moderate increases in the cytokine interleukin-6 (IL-6) in the bloodstream are associated with CHD risk. IL-6, which is produced very early in inflammation, survives only briefly in the human body and its levels fluctuate within individuals. Consequently, its relevance to CHD has been unclear in previous studies.
Between 1967 and 1991, nearly 25,000 healthy, mainly middle-aged people were enrolled into two studies—the Reykjavik Study and the British Regional Heart Study—and followed for about 20 years, during which time 2,138 people had a first-ever nonfatal heart attack or died of CHD. The researchers measured baseline IL-6 blood levels in these participants and in 4,267 similar participants who had not had a CHD event. They also measured IL-6 levels in 558 healthy participants several years into the study to determine a “regression dilution ratio” for IL-6. This ratio gives an idea of the year-to-year consistency of IL-6 levels. When the researchers used this ratio to estimate the impact of prolonged increases in IL-6 levels on CHD, they found that increased long-term IL-6 levels more than doubled the risk for CHD in their study populations. The researchers then combined these new results with those of 15 previous relevant studies. This combined analysis indicated very similar findings to those in the new data.
These findings indicate prolonged moderate increases in IL-6 levels are associated with risk of CHD as strongly as several major established risk factors, including blood pressure and blood cholesterol levels, but whether there is a cause-and-effect relationship remains unknown. More studies are needed to find out whether this result is generalisable to other populations, but the broad agreement between the Icelandic and British studies suggests that they should be. This study renews interest in IL-6–mediated inflammatory pathways and CHD.
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As atherosclerosis may be an inflammatory condition [
We report new data on IL-6 levels from two population-based prospective cohorts, the Reykjavik Study and the British Regional Heart Study (BRHS), which together comprise 24,230 predominantly middle-aged individuals with an average of almost 20 years of follow-up per participant. After exclusion of participants with any evidence of baseline coronary disease or stroke, 2,138 incident cases of CHD were available for the present analyses, more than four times as many CHD cases as in the largest previous study [
The Reykjavik Study and the BRHS were initiated in 1967 and 1978, respectively, and have each been described in detail previously [
IL-6 measurements were made in the Reykjavik Study and BRHS on available serum samples, using a sensitive enzyme-linked immunosorbent assay (ELISA; R & D Systems) in the Glasgow laboratory by the same technicians blinded to participants' disease status. The intra-assay coefficient of variability was 7%, and the inter-assay coefficient of variability was 8%. Measurements were made in pairs of samples from a randomly selected subset of baseline participants in each study, comprising 258 participants in the BRHS (samples collected at a median interval of about 4 y apart) and 300 participants in the Reykjavik Study (samples collected at a median interval of about 12 y apart). Because the temperature of storage of the initial BRHS samples was −20 °C, whereas it was −70 °C at the resurvey, there was scope in this study for slight overestimation of within-person variability in IL-6 levels, encouraging comparison of its findings with those from the Reykjavik Study in which conditions at the two surveys were identical. Lipid and other biochemical measurements involved standard assays, as previously described [
In both the Reykjavik Study and BRHS, two or three control participants were randomly selected and frequency matched to incident CHD cases in 5-y age bands (and, in the Reykjavik Study, on calendar year of recruitment and sex; and in the all-male BRHS by town of residence), thereby obtaining the same joint frequency distributions of these factors among controls and cases. To limit any biases due to preexisting disease, prespecified principal analyses were restricted to the 2,138 individuals with CHD and 4,267 control participants who did not have baseline evidence of CHD or stroke (i.e., without baseline ECG abnormalities or self-reported prevalent MI, stroke, or angina) in a nested case–control comparison. Subsidiary analyses excluded patients who had CHD outcomes in the first 5 y of follow-up. Odds ratios for CHD per 2 standard deviations (SDs) increase in the natural logarithm (loge) of IL-6 were calculated using unconditional logistic regression (Stata, version 9). The odds ratios for a 2 SD change is similar to a comparison of extreme thirds of IL-6 values in a population. Analyses to investigate the shape of the IL-6–CHD association were conducted for groups defined by fifths of baseline IL-6 values in controls, with corresponding 95% CIs estimated from floating variances that reflect the amount of information underlying each group (including the reference group) [
Data from paired measurements in the Reykjavik Study, which coincided with approximately the midpoint of this study's follow-up duration, were used to quantify and to correct for within-person variability in IL-6 and other risk factors, which are likely to be measured with error owing to both within-person biological variability and laboratory variability. Adjusted regression dilution ratios were calculated by Rosner's regression method [
A systematic review of prospective, population-based studies of circulating IL-6 levels and CHD risk was conducted according to QUOROM (Quality of Reporting of Meta-analyses) guidelines (
Prospective (cohort or “nested” case–control) studies based in essentially general populations (i.e., where participants were not selected on the basis of preexisting disease) with samples taken at baseline (i.e., prior to the occurrence of events) were eligible for inclusion in the current review. Analyses were restricted to studies with at least 1 y of follow-up and with outcomes defined as MI or coronary death. Three studies of IL-6 (comprising approximately 450 CHD cases or 7% of the total) [
In the Reykjavik study, the median duration of follow-up of participants with CHD and control participants were 14 y and 23 y, respectively; in the BRHS, the corresponding durations were 9 y and 17 y, respectively. IL-6 levels were significantly higher in those with CHD than in control individuals in both the Reykjavik Study and in the BRHS, as were levels of several established cardiovascular risk factors (
Baseline Characteristics of Incident CHD Cases and Controls without Known Evidence of Coronary Disease at Baseline Nested within the Reykjavik Study and BRHS
Relative Odds of CHD per 2 SD Increase in Baseline Loge IL-6 Levels in Participants without Known Coronary Disease at Baseline in the Reykjavik Study and the BRHS
Fifths were calculated on the basis of the distribution of controls in the combined dataset. CIs were calculated using floating variances. Sizes of data markers are proportional to the inverse of the variance of the odds ratios. Adjusted for cohort, age, sex, recruitment period, and town of recruitment.
The regression dilution ratio for loge IL-6 was 0.41 (0.28–0.53) in 258 individuals who provided paired measurements on average 4 y apart in the BRHS, similar to the regression dilution ratio of 0.35 (0.23–0.48) in 300 individuals who provided paired measurements on average 12 y apart in the Reykjavik Study (mean loge IL-6 levels at baseline and at resurvey were 0.76 [SD 0.58] and 0.98 [SD 0.64] pg/ml, respectively, in BRHS and 0.63 [SD 0.70] and 0.88 [SD 0.68] pg/ml, respectively, in the Reykjavik Study). Similar point estimates for the regression dilution ratios of loge IL-6 levels over 4- and 12-y intervals may reflect that much of the variability in this marker is related to shorter-term rather than longer-term factors, although CIs around these estimates were relatively wide. As there were no signification associations between within-person differences in loge IL-6 levels and time intervals between measurements (
Regression Dilution Ratios (95% CI) for IL-6, Other Measured Inflammatory Markers, and Some Established Cardiovascular Risk Factors, Based on Paired Measurements in Up to 380 Participants in the Reykjavik Study Who Provided Samples Approximately 12 Years Apart
(A) Baseline exposure adjusted for baseline confounders.
(B) Usual exposure adjusted for baseline confounders.
(C) Usual exposure adjusted for usual confounders.
Sizes of data markers are proportional to the inverse of the variance of the odds ratios. Baseline (A) refers to measured values just at the initial examination. Usual (B and C) refers to an estimate of the long-term average values by employing data on repeat measurements from the Reykjavik Study (see
We identified 17 relevant studies [
Characteristics of 17 Prospective Studies of Circulating IL-6 Concentrations and CHD Risk in Essentially General Populations
(A) Baseline exposure adjusted for baseline confounders.
(B) Usual exposure adjusted for baseline confounders.
Baseline refers to measured values just at the initial examination. Usual refers to an estimate of the long-term average values. The correction for regression dilution (see
+, adjusted for age and sex; ++, adjusted for age, sex, and smoking status; +++, adjusted for age, sex, smoking status, and other established CHD risk factors; FINRISK, Finnish National Risk Factor Survey; HPFUS, Health Professionals' Follow-up Study; MONICA, MONItoring of trends and determinants in Cardiovascular disease; PRIME, Prospective Epidemiological Study of Myocardial Infarction; WHIOS, Women's Health Initiative Observational Study; WOSCOPS, West of Scotland Coronary Prevention Study.
Previous reports on IL-6 levels and CHD have not been able to correct for within-person fluctuations in the levels of this short-acting cytokine, potentially yielding biased estimates. The present study, which made such correction on the basis of paired measurements of IL-6, indicates that long-term average (“usual”) IL-6 levels are about as strongly associated with CHD risk as are some major established risk factors. Increasing IL-6 levels are associated with progressively increasing odds ratios for CHD (i.e., there are continuous, approximately log-linear relationships). There are moderate associations of IL-6 levels with some established risk factors (notably smoking, diabetes, and dyslipidemia) and with several downstream inflammatory markers, consistent with the key role of IL-6 in mediating inflammatory cascades [
By showing that pathways mediated by long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, the current data reinforce interest in the connection between inflammatory pathways and cardiovascular diseases. The data also underscore the need for investigations of proximal inflammatory mediators that can quantify and correct for within-person variability. Serious underestimation is likely without such correction because, as demonstrated in the current study, the variability in IL-6 levels is substantially higher than for downstream inflammatory markers and several established CHD risk factors. Hence, given the central role of IL-6 levels in inflammatory pathways and its continuous association with CHD risk, it warrants further investigation as a plausible potential therapeutic target. There are initial reports of reductions in circulating IL-6 concentrations in randomised trials of statins, although these agents have other effects, notably lowering low-density lipoprotein cholesterol [
The strengths and potential limitations of the present report merit careful consideration. The current study reports new data from two population-based prospective cohorts comprising more than four times as many patients with first-ever CHD than in the previous largest report. Both the Reykjavik Study and BRHS identified participants in population registers, involved high response and follow-up rates, and involved robust ascertainment of incident MI and coronary death. Their broadly similar results support the generalisability of the current findings. Assay methods used in the current study were similar to those in earlier reports, yielding similar median IL-6 levels (
In comparison with a previous nonquantitative review [
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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Mark B. Pepys, Kausik Ray, and Emanuele Di Angelantonio commented helpfully; J. Wheeler provided statistical support; E. Poorhang and P. Welsh conducted IL-6 assays.
British Regional Heart Study
coronary heart disease
confidence interval
electrocardiogram
interleukin-6
myocardial infarction
standard deviation