The Interleukin-6 Receptor as a Target for Prevention of Coronary Heart Disease: A Mendelian Randomisation Analysis

Study Questions:

What is the effect of interleukin-6 receptor (IL6R) signaling on coronary heart disease (CHD)?

Methods:

Single nucleotide polymorphisms (SNPs) in the IL6R were determined to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of CHD. Genetic findings were compared with the effects of the IL6 antibody, tocilizumab, reported in trials involving patients with rheumatoid arthritis.

Results:

In 133,449 individuals, an IL6R SNP (rs7529229) marking a nonsynonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased IL6 concentrations (9.45% per allele) as well as reduced C-reactive protein (decrease 8.35% per allele) and fibrinogen concentrations (0.85% decrease per allele). This pattern was consistent with IL6R blockade from infusions of tocilizumab in patients with rheumatoid arthritis studied in randomized trials. In 25,458 CHD cases and 100,740 controls, the IL6R rs7529229 SNP was associated with reduced odds of CHD events (per allele odds ratio 0.95, p = 1.53 × 10–5).

Conclusions:

The authors concluded that IL6R signaling seems to have a causal role in the development of CHD.

Perspective:

Although associations with IL6 and CHD have been previously demonstrated, causality between CHD and IL6R signaling has been unclear. By showing that a functional IL6R gene variant is associated with reduced CHD risk, this study provides strong support for IL6R as a valid therapeutic target for the prevention of CHD. Since tocilizumab is already in use in patients with rheumatoid arthritis, and leads to similar changes in biomarkers as the gene variant, one might predict that this drug will have beneficial vascular effects. The safety and magnitude of benefit of this drug (or other IL6R antagonists) will need to be tested in further trials.

Clinical Topics: Prevention, Atherosclerotic Disease (CAD/PAD), Novel Agents

Keywords: Antibodies, Monoclonal, Humanized, Odds Ratio, Coronary Artery Disease, Interleukin-6, Coronary Disease, Primary Prevention, C-Reactive Protein, Polymorphism, Single Nucleotide, Biological Markers, Fibrinogen, Receptors, Interleukin-6


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