Studies Provide Strongest Evidence To Date For Causative Role of Inflammation in Heart Disease

Two large new meta-analyses published in the Lancet provide the first strong evidence demonstrating a cause-and-effect relationship between a specific inflammatory protein and the development of coronary heart disease (CHD). Both studies illuminate the role of interleukin-6 receptor (IL6R) by focusing on the common Asp 358Ala variant of the IL6R gene. The variant is known to dampen the inflammatory effect of IL6R.

In the first study, members of the IL6R Genetics Consortium Emerging Risk Factors Collaboration found that Asp358Ala was present in 39% of the population, and was not significantly related to other risk factors. 358Ala increased concentrations of IL6R and interleukin 6 and decreased concentrations of CRP and fibrinogen. Importantly, each copy of 358Ala was associated with a 3.4% reduction in the risk of CHD.

In the second study, members of the Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium performed a Mendelian randomization to analyze the impact on CHD of tocilizumab, an anti-inflammatory monoclonal antibody that blocks IL6R, in patients with rheumatoid arthritis (RA). They found that the effect of the 358Ala variant was similar to the effect of tocilizumab in RA trials and resulted in increased levels of IL-6 and decreased levels of CRP and fibrinogen. The investigators also observed a significant reduction in the risk of CHD in a second analysis of more than 25,000 people with CHD people and 100,000 controls. They concluded that IL6R signaling appears to “have a causal role in development” of CHD and that “IL6R blockade could provide a novel therapeutic approach to prevention” of CHD.

In an accompanying comment, S Matthijs Boekholdt and Erik SG Stroes write that the presence of inflammation in atherogenesis has long been recognized, but it has been difficult to establish a causative role. Although CRP has been shown to predict risk, an earlier Mendelian randomization analysis failed to establish a causative role. Further, they note, “there is currently no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk.” The consistent results of the two Lancet papers, they write, “lend strong support to the concept that inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk.”

Paul Ridker offered the following perspective on the studies:

The new studies are both very important for the inflammatory hypothesis of atherothrombosis as they provide clear linkage between IL-6, its receptor, and clinical events. Moreover, the new data provide confirmatory evidence to consider agents that alter the IL-6 pathway as potential therapeutic agents. As one example, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) that my group coordinates is evaluating a novel monoclonal antibody that targets IL-1-beta and results in lower levels of fibrinogen, CRP, and IL-6. CANTOS is underway in 25 countries and is a hard outcomes trial in secondary prevention. So this field is becoming very exciting and the new data support the concept of lowering inflammation to potentially lower vascular risk.

Rick Lange generously offered his own summary and analysis of the papers:

Despite strong evidence associating inflammation with atherosclerosis, a causal role for C-reactive protein or fibrinogen in atherogenesis has remained highly controversial, especially since inflammation is linked with other conditions (i.e., obesity, hypertension, dyslipidemia, diabetes, smoking, etc.) that are known to increase cardiovascular risk.  In addition, Mendelian randomization analyses showed that variants in the gene for C-reactive protein associated with high concentrations of the protein were not associated with risk of coronary heart disease, making a causal role for C-reactive protein itself in atherogenesis less likely. Lastly, there is currently no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk.

The 2 Lancet studies report data from individuals with genetic abnormalities in the inteleukin-6 receptor gene (ILR6) that lead to reduced concentrations of the membrane-bound form of interleukin 6 (i.e., hence reduced activation of the inflammatory pathways in hepatocytes, monocytes and macrophages that are upstream of C-reactive protein).  This genetic difference lead to (a) an anti-inflammatory effect (lower serum levels of C-reactive protein and fibrinogen) and (b) a reduction of coronary heart disease (3.4% to 5% per-allele reduction) and (c) no change in BP, lipids, obesity, hyperglycemia or smoking).  So this is the strongest evidence to date that inflammation has a causative role in cardiovascular disease. Whether or not inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk is a separate issue, since anti-inflammatory strategies may increase the risk of infection or malignancy.

Here is the press release from the Lancet:

Genetic studies lay the foundations for anti-inflammatory drugs to prevent heart disease (The Lancet)

Two large international meta-analyses published Online First in The Lancet provide compelling new evidence that interleukin-6 receptor (IL6R), a protein involved in inflammatory signaling, has a causal role in the development of coronary heart disease (CHD). The findings suggest that drugs that target this specific inflammatory mechanism (ie, IL6R-mediated signaling) might also be effective in combating CHD. One such drug, tocilizumab, is already commonly used to treat rheumatoid arthritis*.

CHD is the leading cause of death worldwide. It is caused by atherosclerosis, a build-up of fatty material in the walls of arteries. There has been considerable interest in the role of inflammation in atherosclerosis, but until now, a direct causal link with a specific inflammatory biomarker has not been shown.

Previous studies have reported associations between various blood measures of inflammation and the risk of heart attacks, but human genetic studies have suggested that these simply reflect correlations rather than cause-and-effect relationships.

By contrast, in the first Article, the IL6R Genetics Consortium and Emerging Risk Factors Collaboration have reported that a genetic variation responsible for dampening inflammation reduces the risk of heart disease.

In particular, the researchers analysed genetic and biomarker information from over 200 000 people in 82 studies to assess whether a functional genetic variant (Asp358Ala) in the IL6R gene, known to control IL6R signaling, might affect susceptibility to CHD. The 358Ala allele was associated with a clear anti-inflammatory effect, shown by reductions in levels of C-reactive protein and fibrinogen in the blood, as well as a 3.4% reduction in CHD risk for each copy of 358Ala inherited.

The authors say: “These results support the inflammation hypothesis in CHD and encourage exploration of modulation of IL6R pathways as a means to prevent CHD.”

In a second Article, the IL6R Mendelian Randomisation Analysis Consortium analysed data from 40 studies involving almost 133 500 participants to examine whether using a drug to block the IL6 receptor from exerting its pro-inflammatory effects might reduce the risk of CHD in the general population.

Using Mendelian randomisation** they identified that a single-nucleotide polymorphism (SNP) gene variation in IL6R (rs7529229), which represents the Asp358Ala variant, had effects on several inflammatory markers and related pathways consistent with effects reported in trials blocking the IL6R in patients with rheumatoid arthritis using the drug tocilizumab.

A further meta-analysis predicted the same (rs7529229) variant was associated with a lower risk of CHD in a total of 25 458 CHD cases and 100 740 controls, corresponding to a 5% reduction in CHD risk for each copy inherited.

The authors conclude: “IL6R blockade could provide a novel therapeutic approach to prevention of CHD that warrants testing in suitably powered randomised trials.”

In an accompanying Comment, Matthijs Boekholdt and Erik Stroes from the Academic Medical Center, Amsterdam, the Netherlands say: “Collectively, these large-scale and highly consistent results lend strong support to the concept that inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk.”