Genetic studies lay the foundations for anti-inflammatory drugs to prevent heart disease

March 13, 2012

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 Collaboration have reported that a responsible for dampening inflammation reduces the .

In particular, the researchers analysed genetic and 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 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 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."

Explore further: Low-risk patients screened for heart disease tend to receive more preventive care and testing

More information: … (11)61931-4/abstract … (12)60110-x/abstract

* Tocilizumab is known to reduce articular inflammation and promote disease remission in rheumatoid arthritis.
**Mendelian randomisation to validate drug targets uses variants in gene encoding of a drug target to profile the mechanism-based effects of pharmacological modification of that target, providing randomised evidence for the likely effectiveness of a new treatment without the potential risks of exposure to a novel drug or costs of a randomised trial.

Related Stories

Low-risk patients screened for heart disease tend to receive more preventive care and testing

May 23, 2011
Screening for coronary heart disease (CHD) among individuals at low risk of the condition is associated with increased use of medications (such as aspirin and statins) and increased additional testing, but no difference in ...

Chemical found in crude oil linked to congenital heart disease

April 30, 2011
While it may be years before the health effects of the 2010 oil spill in the Gulf of Mexico are known, a new study shows that fetal exposure to a chemical found in crude oil is associated with an increased risk of congenital ...

Recommended for you

Could aggressive blood pressure treatments lead to kidney damage?

July 18, 2017
Aggressive combination treatments for high blood pressure that are intended to protect the kidneys may actually be damaging the organs, new research from the University of Virginia School of Medicine suggests.

Quantifying effectiveness of treatment for irregular heartbeat

July 17, 2017
In a small proof-of-concept study, researchers at Johns Hopkins report a complex mathematical method to measure electrical communications within the heart can successfully predict the effectiveness of catheter ablation, the ...

Concerns over side effects of statins stopping stroke survivors taking medication

July 17, 2017
Negative media coverage of the side effects associated with taking statins, and patients' own experiences of taking the drugs, are among the reasons cited by stroke survivors and their carers for stopping taking potentially ...

Study discovers anticoagulant drugs are being prescribed against safety advice

July 17, 2017
A study by researchers at the University of Birmingham has shown that GPs are prescribing anticoagulants to patients with an irregular heartbeat against official safety advice.

Protein may protect against heart attack

July 14, 2017
DDK3 could be used as a new therapy to stop the build-up of fatty material inside the arteries

Heart study finds faulty link between biomarkers and clinical outcomes

July 14, 2017
Surrogate endpoints (biomarkers), which are routinely used in clinical research to test new drugs, should not be trusted as the ultimate measure to approve new health interventions in cardiovascular medicine, according to ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.