Gene Studies: IL-6 Pathway Has Causal Role in Heart Disease

March 15, 2012

March 13, 2012 (Cambridge and London, United Kingdom) — New analyses from two large genetics consortia provide the first real evidence that the interleukin-6 (IL-6) receptor protein has a causal role in the development of coronary heart disease (CHD) [1,2]. The findings are important, say the researchers, because they indicate that targeting IL-6-receptor–mediated signaling might be an effective pharmacological intervention in heart disease.

"Any physician will be able to tell you that inflammation is important in heart disease and atherosclerosis, but it's been difficult to actually find places where we could intervene on that system. So this is quite exciting, because it is one of the first inflammation-related genetic findings, with the potential of a novel class of agents that we could use," says Dr Adam S Butterworth (University of Cambridge, UK), a member of one of the large teams that has just published the new research.

This is quite exciting, because it is one of the first inflammation-related genetic findings, with the potential of a novel class of agents that we could use.

Dr Daniel I Swerdlow (University College London, UK), who worked with the other big group, concurs. "Our work shows that signaling at the IL-6 receptor is likely to play a causal role in atherogenesis and coronary heart disease and that the IL-6 receptor is a potential pharmacological target," he told heartwire . Both groups note that a drug that blocks the IL-6 receptor, tocilizumab (Actemra, Roche), is marketed for rheumatoid arthritis but is unlikely to be a good candidate for prevention of CHD for a variety of reasons.

Swerdlow adds that the fact that his consortia's results appear to be consistent with those of Butterworth and colleagues "is reassuring and adds weight to the findings." Both papers are published online March 13, 2012 in the Lancet.

And in a comment accompanying them [3], Drs S Matthijs Boekholdt and Erik SG Stroes (Academic Medical Center, Amsterdam, the Netherlands) agree: "These large-scale and highly consistent results . . . provide solid evidence for a causal role of the proinflammatory interleukin-6 pathway in determining risk of CHD."

Findings open door to treatment and shed light on potential mechanisms

Commenting on the first paper, by the IL6R Genetics Consortium and Emerging Risk Factors Collaboration, Butterworth notes that the IL-6 pathway and its receptor lie slightly upstream of C-reactive protein (CRP) and fibrinogen in the inflammatory cascade.

"It's been known for a while that levels of IL-6 protein in the blood are associated with heart disease, but what wasn't previously known was whether or not that was just a marker of disease that happened to be correlated or whether there was some sort of cause-and-effect relationship," he explained.

The consortium looked at a common variant in the gene that encodes the receptor for IL-6 (IL6R), the Asp358Ala variant, which is believed to impair IL6R signaling and dampen inflammation. They studied it in relation to a panel of conventional risk factors and inflammation biomarkers in a collaborative meta-analysis of 82 studies involving 125 122 participants, and they also compared its frequency in 51 441 patients with CHD and in 136 266 controls.

Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycemia, or smoking. In contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% and interleukin-6 by 14.6%, and mean concentration of CRP was reduced by 7.5% and fibrinogen by 1%. For every copy of 358Ala inherited, risk of CHD was reduced by 3.4%.

"The genetics seem to suggest there is a cause-and-effect relationship, which is the key thing, but the work also opens the door to treatment and sheds a bit more light on the potential mechanisms that are going on with this particular variant," says Butterworth.

Same variant mirrors effects of tocilizumab, a drug that blocks IL6R

Swerdlow says he and his group, the Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6RMR) Consortium, also "wondered whether the IL-6 pathway and its receptor might have a role in causing CHD and atherosclerosis. To investigate this, we used the Mendelian randomization principle. We used common genetic variants in IL6R as proxies for a situation where you inhibit the receptor using a drug.

The variant that mirrors the effect of tocilizumab is associated with a lower risk of CHD, [so] our inference is that the IL-6 receptor is likely to be a potential target for prevention of CHD events.

"We looked at associations of this variant in a number of large population-based studies from all over the world with biomarkers of inflammation, with common cardiovascular risk factors, and also with risk of CHD events," he explained.

The same variant as the other consortium used, Asp358Ala, was associated with increased circulating log interleukin-6 concentration (increase per allele 9.45%) as well as reduced CRP (decrease per allele 8.35%) and fibrinogen concentrations (decrease per allele 0.85%).

There was no association of the variant with blood lipids, "but we did see an association with lower systolic and diastolic blood pressure," Swerdlow said.

And the variant was associated with a decreased odds of CHD (per-allele odds ratio 0.95).

The consortium then went on to compare their findings with the results reported by randomized controlled trials of tocilizumab, which specifically inhibits the signaling of the IL-6 receptor.

"What we saw was a very close concordance between the effects of the genetic variant and the effects of the drug on the biomarkers, so we conclude from this that the genetic variant was a reliable instrument for inhibition of signaling in the IL-6 receptor," says Swerdlow.

"And because we saw that the variant that mirrors the effect of tocilizumab is associated with a lower risk of CHD, our inference from putting all of this together is that the IL-6 receptor is likely to be a potential target for prevention of CHD events."

Expectations are raised but intervening in inflammation is "tricky"

Butterworth further explains why the new analyses are so important. "These two papers are the first to really focus in such detail on this one particular genetic variant and to bring in the other information — not just looking at the genetic variant and heart disease outcomes, but, for example, looking at its effect on protein levels in the blood and on conventional cardiovascular risk factors," he says.

"And as well as the therapeutic angle, it's quite interesting from the scientific point of view that these papers are starting to shed light on the mechanism by which this one letter change in the DNA is leading to different levels of these proteins and therefore leading to different levels of heart disease risk. By bringing together all this information, we are really starting to make some headway into that story."

However, both researchers caution that tocilizumab may not be of any use in CHD, because it has to be given by monthly intravenous infusion, and it also appears to raise lipid levels, although this could be an effect specific to rheumatoid-arthritis patients, Swerdlow noted. Or, says Butterworth, it could be that the lipid raising could be specific to this particular drug and may not be a class effect of other similar agents or that it could be easily managed with statins, he added.

Nevertheless, he cautions, "Intervening in an area like inflammation is potentially quite tricky."

The editorialists agree: "The delicate risk/benefit balance between inappropriate inflammation and anti-inflammatory interventions has confronted us with numerous unresolved issues, emphasizing the need for detailed knowledge about inflammatory pathways contributing to atherosclerotic complications."

Regardless, the present findings raise "expectations for ongoing trials testing anti-inflammatory strategies for cardiovascular risk reduction," they conclude.

Butterworth and Swerdlow have no conflicts of interest. Disclosures for the coauthors are listed in the paper. The editorialists report no conflicts of interest.


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