The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
Bottom Line: 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.UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
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Mentions: The IL6R rs7529229 SNP displayed additive associations with circulating concentrations of interleukin 6, C-reactive protein, and fibrinogen (figure 1, table). Circulating interleukin-6 concentration increased with each additional copy of the minor allele at rs7529229 (relative increase in geometric mean log interleukin-6 concentration per allele 9·45%, 95% CI 8·34–10·57; p=8·41×10−68), whereas the concentrations of C-reactive protein and fibrinogen decreased per minor allele (relative decrease in geometric mean log C-reactive protein 8·35%, 95% CI 7·31–9·38, and fibrinogen 0·85%, 0·60–1·10, per minor allele). The associations with interleukin 6 and C-reactive protein were consistent across study-specific subgroups (appendix pp 34–37) with no evidence of genotype-by-subgroup interaction (p>0·05 for all analyses). Concentration of soluble IL6R increased per minor allele (table). The functional rs8192284 variant showed associations with interleukin 6, C-reactive protein, and fibrinogen that were directionally concordant with those of rs7529229 in the Whitehall II study (appendix p 24). No significant association was noted between the rs7529229 SNP and concentration of total, LDL, and HDL cholesterol or triglycerides in analyses including up to 114 615 individuals (table).