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

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Abstract

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.

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