title: Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy.
abstract: Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.
authors.affiliation: Medical Department, Viborg Regional Hospital, Viborg, Denmark.|Biomedicine, University of Aarhus, Aarhus, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Bank
authors.affiliation: Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.|Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: P S
authors.identifier: 0000-0001-5656-0427
authors.initials: PS
authors.lastname: Andersen
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Burisch
authors.affiliation: Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Pedersen
authors.affiliation: Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Roug
authors.affiliation: Medical Department, Køge Hospital, Køge, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Galsgaard
authors.affiliation: Department of Surgery, Hillerød Hospital, Hillerød, Denmark.
authors.forename: S Y
authors.initials: SY
authors.lastname: Turino
authors.affiliation: Medical Department, Sydvestjysk Hospital, Esbjerg, Denmark.|Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark.
authors.forename: J B
authors.initials: JB
authors.lastname: Brodersen
authors.affiliation: Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Rashid
authors.affiliation: Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.
authors.forename: B K
authors.initials: BK
authors.lastname: Rasmussen
authors.affiliation: Department of Hepato-Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Avlund
authors.affiliation: Medical Department, Slagelse Hospital, Slagelse, Denmark.
authors.forename: T B
authors.initials: TB
authors.lastname: Olesen
authors.affiliation: Department of Respiratory Diseases B, Institute for Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: H J
authors.initials: HJ
authors.lastname: Hoffmann
authors.affiliation: Biomedicine, University of Aarhus, Aarhus, Denmark.
authors.forename: B A
authors.initials: BA
authors.lastname: Nexø
authors.affiliation: Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.|Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.|Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
authors.forename: J
authors.identifier: 0000-0002-2718-9320
authors.initials: J
authors.lastname: Sode
authors.affiliation: National Research Centre for the Working Environment, Copenhagen, Denmark.
authors.forename: U
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Medical Department, Viborg Regional Hospital, Viborg, Denmark.|Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.|Research Unit for Molecular Diagnostic, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark.|OPEN Odense Patient Data Explorative Network, Odense University Hospital, Odense, Denmark.
authors.forename: V
authors.initials: V
authors.lastname: Andersen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics*; D020382:Interleukin-18 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051198:Toll-Like Receptor 5 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: C000589760:IL18 protein, human; D020382:Interleukin-18; C495346:TLR5 protein, human; C439524:TNF protein, human; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma