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 [3
]. The current findings do not, of course, establish causality, but they may have implications for understanding disease mechanisms and for further research strategies.
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 [45
]. Future investigations should involve complementary strategies to help judge causality, such as large-scale studies of specific genetic markers as proxies for circulating IL-6 levels [48
] (although it is now uncertain whether the −174 G/C IL-6
polymorphism is materially correlated with IL-6 levels [49
]) and, possibly, use of selective IL-6 antagonists in early randomized trials [50
], although the pleiotropic actions of IL-6 could complicate such an approach.
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 (). Although the current studies involved more prolonged blood storage than previous studies, they produced associations with CHD risk at least as strong as in earlier studies, arguing against underestimation due to sample degradation. Paired IL-6 (and other) measurements enabled approximate correction for within-person variability in a way that implies that long-term average IL-6 values are relevant to CHD risk, consistent with prevailing hypotheses of sustained low-grade inflammation, but it is not clear why mean loge IL-6 levels were generally higher at resurvey examinations.
In comparison with a previous nonquantitative review [22
], the current meta-analysis involved almost five times as many incident CHD cases from population-based prospective studies (thereby enhancing statistical power), strictly defined CHD as MI or fatal CHD (thereby enhancing accuracy of disease classification), excluded (where possible) people with prevalent cardiovascular disease (thereby limiting potential biases), and explored in detail potential sources of heterogeneity (thereby probing possible causes of study diversity). This updated review suggests that the apparently divergent estimates reported in earlier studies were probably chiefly due to random error. Further studies are needed to test whether associations of IL-6 with CHD are importantly modified by lipid concentrations, as suggested by exploratory analyses in the current report. Studies are also needed with serial measurements in larger numbers of participants over different intervals in order to assess IL-6 variability in greater detail (e.g., assessment of any changes in mean levels and variability over time). This information will enable study-specific and time-dependent correction for regression dilution [23
], whereas in the current meta-analysis the correction factor was derived from repeat measurements in only the Reykjavik Study. Adjustment for within-person variability in both exposure and confounder levels across all available studies will require access to individual participant data, as demonstrated by such adjustment in the current analyses of the Reykjavik Study and BRHS.
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.