Bank, S5; Andersen, P S6; Burisch, J7; Pedersen, N8; Roug, S9; Galsgaard, J10; Turino, S Y11; Brodersen, J B12; Rashid, S13; Rasmussen, B K14; Avlund, S15; Olesen, T.B.16; Hoffmann, H J21; Thomsen, Marianne Kragh22; Thomsen, V Ø17; Frydenberg, M23; Nexø, B A24; Sode, J18; Vogel, U19; Andersen, V20
1 Department of Clinical Medicine - Department of Respiratory Diseases and Allergy, Department of Clinical Medicine, Health, Aarhus University2 Department of Clinical Medicine - Klinisk Mikrobiologi, Department of Clinical Medicine, Health, Aarhus University3 Department of Public Health - Department of Biostatistics, Department of Public Health, Health, Aarhus University4 Department of Biomedicine - Forskning og uddannelse, Øst, Department of Biomedicine, Health, Aarhus University5 Department of Molecular Biology, Faculty of Science, Aarhus University, Aarhus University6 Afdeling for Nationaløkonomi, Faculty of Social Sciences, Aarhus University, Aarhus University7 Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.8 SUN-IT, IT-service, Faculty of Health Sciences, Faculty of Health Sciences, Aarhus University, Aarhus University9 Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.10 Medical Department, Køge Hospital, Køge, Denmark.11 Medical Department, Hillerød Hospital, Hillerød, Denmark.12 Studieadministrationen, Aarhus School of Business, Aarhus BSS, Aarhus University13 Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark.14 Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.15 Medical Department V, Aarhus University Hospital, Aarhus, Denmark.16 Medical Department, Slagelse Hospital, Slagelse, Denmark.17 Department of the History of Ideas, Faculty of Humanities, Aarhus University, Aarhus University18 1] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark  Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark  Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.19 Institute of Environmental and Occupational Medicine, Faculty of Health Sciences, Aarhus University, Aarhus University20 1] Medical Department, Viborg Regional Hospital, Viborg, Denmark  Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark  Organ Centre, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark  OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.21 Department of Clinical Medicine - Department of Respiratory Diseases and Allergy, Department of Clinical Medicine, Health, Aarhus University22 Department of Clinical Medicine - Klinisk Mikrobiologi, Department of Clinical Medicine, Health, Aarhus University23 Department of Public Health - Department of Biostatistics, Department of Public Health, Health, Aarhus University24 Department of Biomedicine - Forskning og uddannelse, Øst, Department of Biomedicine, Health, Aarhus University
Antitumor 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. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFκB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-α signaling (TNFA (TNF-α) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFκB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P⩽0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFκB through the Toll-like receptor (TLR) pathways, genes regulating TNF-α signaling and cytokines regulated by NFκB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1β, IL-6 and IFN-γ may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting.The Pharmacogenomics Journal advance online publication, 29 April 2014; doi:10.1038/tpj.2014.19.
Pharmacogenomics Journal, 2014, Vol 14, Issue 6, p. 526-34