OTU-006 The interleukin-6 receptor as a drug target in inflammatory bowel disease; a mendelian randomisation study

Introduction Excessive production of interleukin-6 is associated with active inflammatory bowel disease (IBD).1 Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) is licensed for treatment of rheumatoid arthritis.2 Clinical trials of IL6R inhibitors in IBD have been small in numbers, with varying efficacy.3 The IL6R SNP rs2228145 associates with a similar pattern of effects to tocilizumab therapy (higher soluble IL6R, lower c-reactive protein and fibrinogen), making it an attractive genetic instrument for drug target validation.4 Methods We performed a two sample Mendelian randomization study using rs2228145 (a variant associated with impaired IL6R signalling) to evaluate the role of IL6R inhibition for primary prevention of IBD. Gene – soluble IL6R biomarker associations were estimated in 1650 individuals, as a proxy for defective IL6R signalling.5 Gene – IBD associations were estimated in 49 833 cases and 61 630 ancestry matched controls from publically available IBD genome wide association study (GWAS) summary statistics.6 7 Results In a fixed effects meta-analysis of 26 788 cases with Crohn’s disease (CD), 23 045 with ulcerative colitis (UC)) and 61 630 controls, genetically elevated soluble IL6R was associated with decreased odds of Crohn’s disease (CD) (odds ratio (OR) 0.87, 95% CI 0.82–0.92, p=0.00001463) and ulcerative colitis (UC) (OR 0.92, 95% CI 0.89–0.99, p=0.0378) per 2-fold increment. Conclusions On the basis of genetic evidence in human beings, defective IL6R signalling seems to protect against the development of both CD and UC; its inhibition is an attractive drug target suitable for further exploration. Genetic studies in populations could be used more widely to help validate and prioritise novel drug targets or to repurpose existing agents for new therapeutic and preventive uses. References . Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–457. doi:10.1038/ni.3153 . Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 2017;14(5):269–278. doi:10.1038/nrgastro.2016.208 . Coskun M, Vermeire S, Nielsen OH. Novel Targeted Therapies for Inflammatory Bowel Disease. Trends Pharmacol Sci. 2017;38(2):127–142. doi:10.1016/j.tips.2016.10.014 . Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Swerdlow DI, Holmes M V, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379(9822):1214–1224. doi:10.1016/S0140–6736(12)60110-X . IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379(9822):1205–1213. doi:10.1016/S0140–6736(11)61931–4 . Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979–986. doi:10.1038/ng.3359 . de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017;49(2):256–261. doi:10.1038/ng.3760 . Hartwig FP, Borges MC, Horta BL, Bowden J, Davey Smith G. Inflammatory Biomarkers and Risk of Schizophrenia. JAMA Psychiatry. November 2017. doi:10.1001/jamapsychiatry.2017.3191