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Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease
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Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease
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Journal Article
Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease
2014
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Adult
/ Aged
/ Biomedical and Life Sciences
/ Child
/ Denmark
/ Female
/ Humans
/ Inflammatory Bowel Diseases - drug therapy
/ Inflammatory Bowel Diseases - genetics
/ Inflammatory Bowel Diseases - metabolism
/ Male
/ NF-kappa B - antagonists & inhibitors
/ Oncology
/ Polymorphism, Single Nucleotide - drug effects
/ Polymorphism, Single Nucleotide - genetics
/ Signal Transduction - drug effects
/ Signal Transduction - genetics
/ Single nucleotide polymorphisms
/ Tumor Necrosis Factor-alpha - antagonists & inhibitors
