Known vascular risk factors can explain only about half of all cardiovascular disease, leaving much to be discovered about other causes of stroke and heart attack. Persistent inflammation has been implicated in the pathogenesis of coronary heart disease, but causality has not been established for any specific inflammatory mediator.

In The Lancet, two genetics consortia focus on the interleukin-6 pathway upstream of C-reactive protein. In classic IL6R signalling, soluble interleukin-6 activates the membrane-bound receptor in hepatocytes and leucocytes, thereby initiating downstream pro-inflammatory cascades that increase hepatic production of C-reactive protein, fibrinogen, and other acute-phase reactants.  Both groups looked at a common variant in the gene that encodes the receptor for IL6, the Asp358Ala variant, which is believed to impair IL6R signalling and dampen inflammation.

The IL6R Genetics Consortium and Emerging Risk Factors Collaboration studied Asp358Ala in IL6R 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 found no association of Asp358Ala with conventional risk factors.  They also compared its frequency in 51,441 patients with coronary artery disease and in 136,266 controls and found, for every copy of Asp358Ala inherited, the 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%. Importantly, for every copy of Asp358Ala inherited, risk of CHD was reduced by 3.4%.

The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium pooled data from 40 studies including up to 133,449 individuals, and found Asp358Ala was associated with increased circulating log interleukin-6 concentration (increase per allele 9.45%) as well as reduced C-reactive protein (decrease per allele 8.35%,) and fibrinogen concentrations (decrease per allele 0.85%). In 25,458 coronary heart disease cases and 100,740 controls, the IL6R variant was associated with decreased odds of coronary heart disease events (per allele odds ratio 0.95).

The monoclonal antibody tocilizumab (licensed for treatment of rheumatoid arthritis) reduces systemic and articular inflammation through Blockade of IL6R. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium went on to show a similar pattern of effects to the Asp358Ala variant with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials.

Conclusions:

These results from two large genetics consortia provide the first real evidence that the interleukin-6 receptor protein has a causal role in the development of coronary heart disease. The findings are important because they indicate that targeting IL6R blockade could provide a novel therapeutic approach for the prevention of coronary heart disease that warrants testing in randomised trials.

References:

1. IL6R Genetics Consortium and Emerging Risk Factors Collaboration IL-6 pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.
   Lancet 2012; DOI:10.1016/s0140-6736(11)61931-4.
2. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6RMR) Consortium. The IL-6 receptor as a target for prevention of CHD: A Mendelian randomization analysis.
   Lancet 2012; DOI:10.1016/s0140-6736(12)60110-X.