Deciphering Interleukin-6 Receptor's Role in Coronary Heart Disease Prevention: A Mendelian Randomization Approach

Elevated levels of interleukin 6 (IL-6) in the bloodstream have been linked to a heightened risk of coronary heart disease. Tocilizumab, a monoclonal antibody used for rheumatoid arthritis treatment, blocks the IL-6 receptor (IL6R) and has been shown to reduce inflammation systemically and in joints. However, it remains unclear if IL6R blockade can also lower the risk of coronary heart disease.

Utilizing the mendelian randomisation principle, this study employed single nucleotide polymorphisms (SNPs) within the IL6R gene to assess the potential effectiveness and safety of IL6R inhibition for the primary prevention of coronary heart disease. The study involved a comparison of genetic data with the effects observed from tocilizumab treatment in randomized trials with rheumatoid arthritis patients.

The findings from 40 studies, which included a large sample size of up to 133,449 individuals, revealed a significant association between an IL6R SNP (rs7529229) and increased IL-6 levels, as well as reduced C-reactive protein and fibrinogen concentrations. This SNP was linked to a non-synonymous IL6R variant (rs8192284; p.Asp358Ala). The effects observed were in line with those reported from tocilizumab infusions in rheumatoid arthritis patients. Moreover, in a large case-control study involving 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.

The interpretation of these findings suggests that IL6R signaling likely plays a causal role in the development of coronary heart disease, and blocking this pathway could present a new therapeutic strategy for prevention. This approach deserves further investigation in well-designed randomized trials. The use of genetic studies in populations could be more extensively employed to validate and prioritize novel drug targets or to identify new therapeutic applications for existing drugs and targets.

The study was funded by a consortium of organizations including the UK Medical Research Council, British Heart Foundation, Rosetrees Trust, US National Heart, Lung, and Blood Institute, and several others from the UK, US, Netherlands, Sweden, and the European Union.