The interleukin-6 receptor pathway and coronary heart disease
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.IL6R Genetics Consortium and Emerging Risk Factors Collaboration*
Lancet. 2012 Mar 13
The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium.
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
Lancet. 2012 Mar 13.
Inflammation is present in various stages during cardiovascular disease [1,2], but causality with a specific inflammatory mediator has not yet been established. As clinical investigation of these mediators can be difficult due to fluctuations in the circulation , studying the genetic determinants of these factors might be informative as those variants are fixed at conception and indicate a lifelong inflammation status .
Tocilizumab is a monoclonal antibody that blocks both membrane-bound and circulating interleukin-6 receptors (IL6R) and has anti-inflammatory actions beyond reducing CRP and fibrinogen concentrations [5,6]. Whether blocking the IL6R with tocilizumab, a monoclonal antibody, reduces risk of CHD is unknown.
Two meta-analyses provide insight in the role of the interleukin-6 receptor in coronary heart disease.
The first study investigated whether IL6R pathways are causally related to CHD by analyzing human genetic and biomarker data from more than 200 000 participants. In the second study a Mendelian randomization was performed to analyze the impact of tocilizumab on CHD in patients with rheumatoid arthritis (RA).
(1) The Asp358AIa variant in IL6R was present in 39% of the population and not significantly related to other risk factors. 358Ala increased concentrations of IL6R and interleukin 6 and decreased concentrations of CRP and fibrinogen. Each copy of 358Ala was associated with a 3.4% reduction in the risk of CHD.
ConclusionFrom large-scale human genetic and biomarker data a causal association is clear between IL6R-related pathways and CHD, supporting the inflammation hypothesis in this disease. IL6R signaling appears to have a causal role in development of CHD and IL6R blockade could provide a novel therapeutic approach to prevention of CHD.
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. Furthermore, currently there is no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk. The consistent results of the two Lancet papers lend strong support to the concept that inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk.
Editorial comment 
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3. Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008; 5: e78
4. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC). Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 2011; 342: d548.
5. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58: 2968–80.
6. Kremer JL, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate at 1 year: the LITHE study. Arthritis Rheum 2011; 63: 609–21.
7. Boekholdt SM, Stroes ES.The interleukin-6 pathway and atherosclerosis.. Lancet. 2012 Mar 13. [Epub ahead of print]
Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.
Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.
Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0•04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34•3% (95% CI 30•4-38•2) and of interleukin 6 by 14•6% (10•7-18•4), and mean concentration of C-reactive protein was reduced by 7•5% (5•9-9•1) and of fibrinogen by 1•0% (0•7-1•3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3•4% (1•8-5•0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.
Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
Background: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.
Methods: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis.
Findings: In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9•45%, 95% CI 8•34-10•57) as well as reduced C-reactive protein (decrease per allele 8•35%, 95% CI 7•31-9•38) and fibrinogen concentrations (decrease per allele 0•85%, 95% CI 0•60-1•10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0•95, 95% CI 0•93-0•97, p=1•53×10(-5)).
Interpretation: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.