Variation in Interleukin 6 Receptor Gene Associates With Risk of Crohn’s Disease and Ulcerative Colitis

Interleukin 6 (IL6) is an inflammatory cytokine; signaling via its receptor (IL6R) is believed to contribute to development of inflammatory bowel diseases (IBD). The single nucleotide polymorphism rs2228145 in IL6R associates with increased levels of soluble IL6R (s-IL6R), as well as reduced IL6R signaling and risk of inflammatory disorders; its effects are similar to those of a therapeutic monoclonal antibody that blocks IL6R signaling. We used the effect of rs2228145 on s-IL6R level as an indirect marker to investigate whether reduced IL6R signaling associates with risk of ulcerative colitis (UC) or Crohn’s disease (CD). In a genome-wide meta-analysis of 20,550 patients with CD, 17,647 patients with UC, and more than 40,000 individuals without IBD (controls), we found that rs2228145 (scaled to a 2-fold increase in s-IL6R) was associated with reduced risk of CD (odds ratio 0.876; 95% confidence interval 0.822–0.933; P = .00003) or UC (odds ratio 0.932; 95% confidence interval 0.875–0.996; P = .036). These findings indicate that therapeutics designed to block IL6R signaling might be effective in treatment of IBD.

[1]  Valeriia Haberland,et al.  The MR-Base platform supports systematic causal inference across the human phenome , 2018, eLife.

[2]  Peter B. Jones,et al.  Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort , 2017, Brain, Behavior, and Immunity.

[3]  B. Horta,et al.  Inflammatory Biomarkers and Risk of Schizophrenia , 2017, JAMA psychiatry.

[4]  L. Peyrin-Biroulet,et al.  Early intervention in Crohn’s disease: towards disease modification trials , 2017, Gut.

[5]  Tariq Ahmad,et al.  Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease , 2017, Nature Genetics.

[6]  P. Rosenstiel,et al.  Classic IL-6R signalling is dispensable for intestinal epithelial proliferation and repair , 2016, Oncogenesis.

[7]  Jon White,et al.  Selecting instruments for Mendelian randomization in the wake of genome-wide association studies , 2016, International journal of epidemiology.

[8]  Judy H. Cho,et al.  Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations , 2015, Nature Genetics.

[9]  Mulin Jun Li,et al.  Nature Genetics Advance Online Publication a N a Ly S I S the Support of Human Genetic Evidence for Approved Drug Indications , 2022 .

[10]  B. Pierce,et al.  Efficient Design for Mendelian Randomization Studies: Subsample and 2-Sample Instrumental Variable Estimators , 2013, American journal of epidemiology.

[11]  Daniel F. Freitag,et al.  Functional IL6R 358Ala Allele Impairs Classical IL-6 Receptor Signaling and Influences Risk of Diverse Inflammatory Diseases , 2013, PLoS genetics.

[12]  A. Hofman,et al.  Interleukin-6 receptor pathways in abdominal aortic aneurysm , 2012, European heart journal.

[13]  J. Scheller,et al.  The interleukin 6 pathway and atherosclerosis , 2012, The Lancet.

[14]  Jennifer G. Robinson,et al.  The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis , 2012, The Lancet.

[15]  Mark Woodward,et al.  Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies , 2012 .

[16]  Simon A. Jones,et al.  Although IL-6 Trans-Signaling Is Sufficient To Drive Local Immune Responses, Classical IL-6 Signaling Is Obligate for the Induction of T Cell-Mediated Autoimmunity , 2010, The Journal of Immunology.

[17]  T. Hibi,et al.  A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. , 2004, Gastroenterology.