Polymorphisms in the NFkB, TNF‐alpha, IL‐1beta, and IL‐18 pathways are associated with response to anti‐TNF therapy in Danish patients with inflammatory bowel disease. Issue 7 (27th February 2019)

• Record Type: Journal Article
• Authors: Bank, Steffen; Julsgaard, Mette; Abed, Osama Karim; Burisch, Johan; Broder Brodersen, Jacob; Pedersen, Natalia Konstantinovich; Gouliaev, Anja; Ajan, Rullah; Nytoft Rasmussen, Ditlev; Honore Grauslund, Camilla; Roug, Stine; Galsgaard, Julie; Sprogøe Høyer Finsen, David; Lindby, Karoline; Sørensen, Jeanette; Larsen, Lone; Rohr Andersen, Malene; Brandslund, Ivan; Thomassen, Mads; Green, Anders; Bo Bojesen, Anders; Bek Sørensen, Signe; Vogel, Ulla; Andersen, Vibeke
• Other Names: Bergmann Ann Christina investigator.; Andersen Paal Skytt investigator.; Rashid Shaista investigator.; Lund Britta Ørnfelt investigator.; Rasmussen Britt Kaiser investigator.; Avlund Sara investigator.; Nielsen Marie Ødum investigator.; Nilsdotter Bramstång Eva Karolina investigator.; Poulsen Anja investigator.; Rudbeck‐Resdal Ditte investigator.; Aamann Luise investigator.; Alexandraki Maria Joanna investigator.; Foroutani Ali investigator.; Molzen Line investigator.; Hatrop Anders investigator.; Rittig Charlotte Siggaard investigator.; Stenbøg Elisabeth investigator.; Hedbäck Nora Elisabeth investigator.; Nielsen Rasmus Gaardskaer investigator.; Schiødt Frank Vinholt investigator.; Carlsen Katrine investigator.; Dessau Ram Benny investigator.; Hoffmann Hans Jürgen investigator.; Nexø Bjørn Andersen investigator.; Sode Jacob investigator.
• Is Part Of: Alimentary pharmacology & therapeutics. Volume 49:Issue 7(2019)
• Page Start: 890
• Page End: 903
• Publication Date: 2019-02-27
• Subjects: Digestive organs -- Diseases -- Treatment -- Periodicals; Digestive organs -- Effect of drugs on -- Periodicals; Gastrointestinal system -- Diseases -- Treatment -- Periodicals; Gastrointestinal system -- Effect of drugs on -- Periodicals; 615.73
• DOI: 10.1111/apt.15187
• Languages: English
• ISSNs: 0269-2813

Abstract

Summary: Background: Anti‐tumor necrosis factor‐α (TNF‐α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one‐third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti‐TNF therapy among patients with CD or UC. Aim: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti‐TNF response. Methods: Fifty‐three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender). Results: Ten SNPs were associated with anti‐TNF response either among patients with CD ( TNFRSF1A (rs4149570) (OR: 1.92, 95% CI: 1.02‐3.60, P = 0.04), IL18 (rs187238) (OR: 1.35, 95% CI: 1.00‐1.82, P = 0.05), and JAK2 (rs12343867) (OR: 1.35, 95% CI: 1.02‐1.78, P = 0.03)), UC ( TLR2 (rs11938228) (OR: 0.55, 95% CI: 0.33‐0.92, P = 0.02), TLR4 (rs5030728) (OR: 2.23, 95% CI: 1.24‐4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27‐0.90, P = 0.02), NFKBIA (rs696) (OR: 1.45, 95% CI: 1.06‐2.00, P = 0.02), and NLRP3 (rs4612666) (OR: 0.63, 95% CI: 0.44‐0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) ( TLR4 (rs5030728) (OR: 1.46, 95% CI: 1.01‐2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65‐0.98, P = 0.03), NFKBIA (rs696) (OR: 1.25, 95% CI: 1.01‐1.54, P = 0.04), NLRP3 (rs4612666) (OR: 0.73, 95% CI: 0.57‐0.95, P = 0.02), IL1RN (rs4251961) (OR: 0.81, 95% CI: 0.66‐1.00, P = 0.05), IL18 (rs1946518) (OR: 1.24, 95% CI: 1.01‐1.53, P = 0.04), and JAK2 (rs12343867) (OR: 1.24, 95% CI: 1.01‐1.53, P = 0.04)). Conclusions: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway ( TLR2, TLR4, and NFKBIA ), the TNF‐α signalling pathway ( TNFRSF1A ), and other cytokine pathways ( NLRP3, IL1RN, IL18, and JAK2 ) were associated with response to anti‐TNF therapy. Our multi‐SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.