Interleukin-6 Receptor and Inflammatory Bowel Disease: A Mendelian Randomization Study

Interleukin 6 (IL-6) is an important inflammatory cytokine.1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar It is reported that IL-6 receptor (IL-6R) signaling is involved in the development of inflammatory bowel diseases (IBD).1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar An IL-6R variant rs2228145 was identified to be associated with increased levels of soluble IL-6R (s- IL-6R), reduced IL-6R signaling and risk of inflammatory disorders.1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 2Garbers C. et al.Biochim Biophys Acta. 2014; 1842: 1485-1494Crossref PubMed Scopus (95) Google Scholar, 3Sarwar N. et al.Lancet. 2012; 379: 1205-1213Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar In a recent issue of Gastroenterology, Parisinos et al1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar performed a Mendelian randomization study to evaluate whether the reduced IL-6R signaling is associated with Crohn’s disease (CD) or ulcerative colitis (UC) using the effect of rs2228145 (C allele) on s- IL-6R level as an instrumental variable. Parisinos et al selected the large-scale genome-wide association study (GWAS) datasets from the International Inflammatory Bowel Disease Genetics Consortium, including 20,550 CD cases and 41,642 controls, as well as 17,647 UC cases and 47,179 controls.1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 4Liu J.Z. et al.Nat Genet. 2015; 47: 979-986Crossref PubMed Scopus (1280) Google Scholar Using a Mendelian randomization method, they found that the genetically increased s-IL-6R level was associated with decreased CD risk (odds ratio [OR], 0.876; 95% confidence interval [CI], 0.822–0.933; P = .00003) and UC risk (OR, 0.932; 95% CI. 0.875–0.996; P = .036).1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar A sensitivity analysis showed that the genetically increased IL-6 level was also associated with decreased CD risk (OR, 0.75; 95% CI, 0.81–0.94; P = .00003) and UC risk (OR, 0.861; 95% CI, 0.71–1.00; P = .038).1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar These findings are important for future studies. Targeting the IL-6R signaling might provide effective treatment of IBD. In their discussion, Parisinos et al1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar pointed out that the nominal association of genetically increased s- IL-6R level with UC (P = .036) requires further validation. In 2017, de Lange et al5de Lange K.M. et al.Nat Genet. 2017; 49: 256-261Crossref PubMed Scopus (527) Google Scholar conducted a GWAS of IBD, conducted a meta-analysis, and published summary statistics of 59,957 samples. We used this publicly available meta-analysis dataset to perform a Mendelian randomization study of the association of IL-6R signaling with CD or UC. The OR as well as 95% confidence CI of CD or UC corresponds with 1 standard deviation in the s-IL-6R or IL-6 levels. The instruments are rs2228145–s-IL-6R and rs2228145–IL-6 associations (per effect allele), which have been described widely in recent studies.1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 3Sarwar N. et al.Lancet. 2012; 379: 1205-1213Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar We define the threshold of statistical significance for the association between s-IL-6R or IL-6 levels and CD or UC risk to be P < .05. All statistical analyses were conducted using the statistical program R (version 3.2.4; R Foundation, Vienna, Austria). In brief, the IL-6R rs2228145 C allele (effect allele) is associated with s-IL-6R level (beta = 0.2949 and standard error [SE] = 0.0148) and IL-6 level (beta = 0.1362 and SE = 0.0176).1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar The beta = ln(OR) is the regression coefficient based on the effect allele. Beta > 0 and Beta < 0 means that this effect allele is associated with increased and reduced s-IL-6R or IL-6R levels, respectively. In the IBD GWAS dataset, the rs2228145 C allele was associated with CD (beta = -0.06; SE = 0.0163; P = .0002243), but not associated with UC (beta = -0.0193; SE = 0.0161; P = .2294).5de Lange K.M. et al.Nat Genet. 2017; 49: 256-261Crossref PubMed Scopus (527) Google Scholar Using the rs2228145-s- IL-6R association, and rs2228145-CD or UC association, our Mendelian randomization study showed that the genetically increased s-IL-6R level was associated with decreased CD risk (OR, 0.8159; 95% CI, 0.7321–0.9093; P = .0002), but not with UC risk (OR, 0.9366; 95% CI, 0.8416–1.0424; P = .2306). Using the rs2228145–IL-6 association and the rs2228145–CD or –UC association, we found that the genetically increased IL-6 level was also associated with a decreased risk of CD (OR, 0.6437; 95% CI, 0.5091–0.8139; P = .0002), but not with UC risk (OR, 0.8679; 95% CI, 0.6884–1.0942; P = .2306). In summary, Parisinos et al1Parisinos C.A. et al.Gastroenterology. 2018; 155: 303-306 e2Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar highlighted the significant association of increased s-IL-6R levels with CD risk (P = .00003), and nominal association of increased s-IL-6R levels with UC risk (P = .036) in their main analysis. In their sensitivity analysis, Parisinos et al reported the significant association of increased IL-6 levels with CD risk (P = .00003), and nominal association of increased IL-6 levels with UC risk (P = .038). Here, we conducted an updated Mendelian randomization study using a recent and large-scale published GWAS dataset. Our findings supported the association of genetically increased s-IL-6R and IL-6 levels with CD, but not UC. Hence, we believe that our findings provide important supplementary validation and information about the role of IL-6R signaling in CD and UC. The authors thank de Lange and colleagues for the CD and UC GWAS summary statistics. ReplyGastroenterologyVol. 156Issue 3PreviewWe would like to thank Liu and colleagues for their letter with regards to our study entitled, “Variation in Interleukin 6 Receptor Gene Associates with Risk of Crohn’s Disease and Ulcerative Colitis.”1 In summary, the additional analysis carried out by the authors of the letter using summary statistics from the more recent (but smaller) de Lange2 meta-analysis supported the association of genetically increased s-IL-6R and IL-6 levels (as a proxy for interleukin 6 receptor blockade) with Crohn’s disease (CD), but not ulcerative colitis (UC). Full-Text PDF