TY - JOUR
T1 - Associations between functional polymorphisms in the NFkappaB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease
AU - Bank, S.
AU - Andersen, P.S.
AU - Burisch, J.
AU - Pedersen, N.
AU - Roug, S.
AU - Galsgaard, J.
AU - Turino, S.Y.
AU - Brodersen, J.B.
AU - Rashid, S.
AU - Rasmussen, B.K.
AU - Avlund, S.
AU - Olesen, T.B.
AU - Hoffmann, H.J.
AU - Thomsen, M.K.
AU - Thomsen, V.O.
AU - Frydenberg, M.
AU - Nexø, B.A.
AU - Sode, J.
AU - Vogel, Ulla Birgitte
AU - Andersen, V.
N1 - SUBMISSIONYEAR:2014
PY - 2014
Y1 - 2014
N2 - [Open access]Antitumor necrosis factor-alpha (TNF-alpha) 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 NFkappaB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-alpha signaling (TNFA (TNF-alpha) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFkappaB (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 (P0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFkappaB through the Toll-like receptor (TLR) pathways, genes regulating TNF-alpha signaling and cytokines regulated by NFkappaB 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-1beta, IL-6 and IFN-gamma 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
AB - [Open access]Antitumor necrosis factor-alpha (TNF-alpha) 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 NFkappaB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-alpha signaling (TNFA (TNF-alpha) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFkappaB (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 (P0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFkappaB through the Toll-like receptor (TLR) pathways, genes regulating TNF-alpha signaling and cytokines regulated by NFkappaB 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-1beta, IL-6 and IFN-gamma 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
U2 - 10.1038/tpj.2014.19
DO - 10.1038/tpj.2014.19
M3 - Tidsskriftartikel
SN - 1470-269X
VL - 14
SP - 526
EP - 534
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
IS - 6
ER -