Inhibition of Interleukin-6 Receptor: A Target of Atherosclerosis Prevention?

A study of a variant of the IL6R gene and a Mendelian randomization for drug-target validation suggest that IL-6 is more than just a risk marker.

A causal role of systemic-inflammation biomarkers such as C-reactive protein (CRP), fibrinogen, and interleukin (IL)-6 in atherogenesis remains controversial. To study causality, genetics researchers use Mendelian randomization to analyze the associations among genotype, phenotype, and disease risk. In an extension of this paradigm — Mendelian randomization for drug-target validation — variants of a gene that encodes a drug target are used to elucidate how the drug affects the target and to distinguish between on-target and off-target effects.

To assess whether the IL-6 receptor (IL6R) is causally related to coronary artery disease (CAD), investigators performed a collaborative meta-analysis of 82 studies of Asp358Ala, a functional genetic variant that affects IL6R signaling. Included were 51,441 CAD patients and 136,226 controls. For every copy of Asp358Ala inherited, mean concentrations of IL6R and IL-6 increased significantly, by 34.3% and 14.6%, respectively; mean concentrations of CRP and fibrinogen decreased by 7.5% and 1.0%, respectively; and CAD risk was reduced by 3.4%.

In another meta-analysis of 40 studies including 133,449 healthy individuals and patients with rheumatoid arthritis (RA), investigators compared genetic findings with the effects of tocilizumab — a monoclonal antibody that reduces systemic and joint inflammation — reported in randomized trials. An IL6R variant in strong linkage disequilibrium with Asp358Ala was significantly associated with increased circulating IL-6 levels as well as reduced CRP and fibrinogen levels. These effects were consistent with those of IL6R inhibition by tocilizumab infusion (4–16 mg/kg every 4 weeks) in RA patients. In 25,458 CAD patients and 100,740 controls, the IL6R variant was associated with a decreased risk for CAD events.

Comment: The findings from these two meta-analyses are very consistent: The IL6R variant attenuated interleukin-6 signaling, leading to a clear anti-inflammatory effect through reduced production of downstream acute-phase proteins such as C-reactive protein and fibrinogen. This effect was accompanied by a reduction in risk for coronary artery disease, suggesting an association between IL6R-related pathways and CAD. Tocilizumab, licensed for long-term treatment of rheumatoid arthritis, produced a pattern of inflammatory biomarker response similar to that associated with the Asp358Ala allele, raising hopes for ongoing trials of anti-inflammatory strategies for primary CAD prevention. In well-defined populations, these types of genetic studies should prove useful in identifying new therapeutic targets for existing agents as well as novel drugs.

— Beat J. Meyer, MD

Published in Journal Watch Cardiology May 30, 2012