Variation in Interleukin 6 Receptor Gene Associates With Risk of Crohn’s Disease and Ulcerative Colitis
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Polymorphisms in the IL6RA gene are associated with susceptibility to both RA and IBD.
“An association between polymorphisms in the IL6RA gene and susceptibility to both RA and IBD have been found (77, 78).”
From T <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [78]
The IL6RA variant rs2228145 is associated with reduced risk of both RA and IBD.
“is associated with reduced risk of both RA (77) and IBD (78).”
From T <sub>H</sub> 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [78]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The support of human genetic evidence for approved drug indications
Nelson, M. R., Tipney, H., Painter, J. L., Shen, J., Nicoletti, P., Shen, Y., Floratos, A., Sham, P. C., Li, M. J., Wang, J., et al. (2015) · Nature Genetics · doi:10.1038/ng.3314 · Cited by 1,666 · see citing works
(2012) · The Lancet · doi:10.1016/s0140-6736(12)60110-x · Cited by 1,146 · see citing works
(2012) · The Lancet · doi:10.1016/s0140-6736(11)61931-4 · Cited by 823 · see citing works
Ferreira, R. C., Freitag, D. F., Cutler, A. J., Howson, J. M. M., Rainbow, D. B., Smyth, D. J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R. M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003444 · Cited by 316 · see citing works
Khandaker, G. M., Zammit, S., Burgess, S., Lewis, G., & Jones, P. B. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2017.11.020 · Cited by 118 · see citing works
Flagged first, then by citations
Research works printed but not linked: 20
- [1]Lissilaa R. J Immunol 185 2010 5512 5521 20870936
- [2]Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium Lancet 379 2012 1214 1224 22421340 PMC3316968
- [3]Ferreira R.C. PLoS Genet 9 2013 e1003444 23593036 PMC3617094
- [4]IL6R Genetics Consortium Emerging Risk Factors Collaboration Lancet 379 2012 1205 1213 22421339 PMC3316940
- [5]Hartwig F.P. JAMA Psychiatry 74 2017 1226 1233 29094161 PMC6583386
- [6]Liu J.Z. Nat Genet 47 2015 979 986 26192919 PMC4881818
- [7]Nelson M.R. Nat Genet 47 2015 856 860 26121088
- [8]Ito H. Gastroenterology 126 2004 989 996 15057738
- [9]Danese S. Gut 66 2017 2179 2187 28874419
- [10]Aden K. Oncogenesis 5 2016 e270 27869785 PMC5141292
- [11]Khandaker G.M. Brain Behav Immun 69 2018 264 272 29197507 PMC5871397
- [12]Swerdlow D.I. Int J Epidemiol 45 2016 1600 1616 27342221 PMC5100611
- [13]Lee J.C. Nat Genet 49 2017 262 268 28067912 PMC5730041
- [14]Scheller J. Lancet 380 2012 338 22841333
- [1]Harrison S.C. Eur Heart J 34 2013 3707 3716 23111417 PMC3869968
- [2]Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium Lancet 379 2012 1214 1224 22421340 PMC3316968
- [3]Pierce B.L. Am J Epidemiol 178 2013 1177 1184 23863760 PMC3783091
- [4]IL6R Genetics Consortium Emerging Risk Factors Collaboration Lancet 379 2012 1205 1213 22421339 PMC3316940
- [5]Hemani G, et al. Elife 2018; pii: e34408. 10.7554/eLife.34408. · DOI · Paper page
- [6]Liu J.Z. Nat Genet 47 2015 979 986 26192919 PMC4881818
Cited by
Sorted by citations
New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
Harbour, S. N., DiToro, D. F., Witte, S. J., Zindl, C. L., Gao, M., Schoeb, T. R., Jones, G. W., Jones, S. A., Hatton, R. D., & Weaver, C. T. (2020) · Science Immunology · doi:10.1126/sciimmunol.aaw2262 · Cited by 151 · see citing works
“Expression of Il23r and other TH17-specific genes is required for several TH17-mediated diseases, including inflammatory bowel disease (IBD) (13–15), psoriasis (16), and ankylosing spondylitis (17), and exposure of TH17 cells to IL-23 is critical for TH17 maintenance and pathogenesis (15, 18–22).”
BackgroundInfluential
- Authors
- Parisinos, C. A., Serghiou, S., Katsoulis, M., George, M. J., Patel, R. S., Hemingway, H., & Hingorani, A. D.
- Affiliations
- University College London (GB)
- Stanford University (US)
- Corresponding author
- Parisinos, Constantinos A.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 155
- Issue
- 2
- Pages
- 303-306.e2
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC6083435
- OpenAlex
- W2804327066
- Cited by
- 67
- References
- 5
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 12 · 2018: 1
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Gastroenterology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (Z/17/Z, 206274/Z/17/Z)
- National Institute for Health and Care Research (NF-SI-0515-10091, CL-2011-11-003)
- British Heart Foundation (FS/14/76/30933, FS/18/5/33319)
- Rosetrees Trust (M202-F2)
- Medical Research Council (MR/K006584/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- IL-6 receptor, rs2228145, Crohn's disease, ulcerative colitis, inflammatory bowel disease, genetic susceptibility, monoclonal antibody therapy
- MeSH terms
- Colitis, Ulcerative, Crohn Disease, Genotype, Humans, Receptors, Interleukin-6, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
