Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease.
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.
1] Medical Department, Viborg Regional Hospital, Viborg, Denmark [2] Biomedicine, University of Aarhus, Aarhus, Denmark.
S
S
Bank
Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
P S
PS
Andersen
Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
J
J
Burisch
Department of Gastroenterology, Herlev Hospital, Herlev, Denmark.
N
N
Pedersen
Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.
S
S
Roug
Medical Department, Køge Hospital, Køge, Denmark.
J
J
Galsgaard
Medical Department, Hillerød Hospital, Hillerød, Denmark.
S Y
SY
Turino
Medical Department, Sydvestjysk Hospital, Esbjerg, Denmark.
J B
JB
Brodersen
Medical Department, Bispebjerg Hospital, Bispebjerg, Denmark.
S
S
Rashid
Medical Department, Nykøbing Falster Hospital, Nykøbing Falster, Denmark.
B K
BK
Rasmussen
Medical Department V, Aarhus University Hospital, Aarhus, Denmark.
S
S
Avlund
Medical Department, Slagelse Hospital, Slagelse, Denmark.
T B
TB
Olesen
Department of Respiratory Diseases B, Institute for Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
H J
HJ
Hoffmann
Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark.
M K
MK
Thomsen
International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark.
V Ø
VØ
Thomsen
Section of Biostatistics, Department of Public health, Aarhus University, Aarhus, Denmark.
M
M
Frydenberg
Biomedicine, University of Aarhus, Aarhus, Denmark.
B A
BA
Nexø
1] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark [2] Clinical Biochemistry, Immunology & Genetics, Statens Serum Institut, Copenhagen, Denmark [3] Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
J
0000000227189320
J
Sode
National Research Centre for the Working Environment, Copenhagen, Denmark.
U
U
Vogel
1] Medical Department, Viborg Regional Hospital, Viborg, Denmark [2] Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark [3] Organ Centre, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark [4] OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.
V
V
Andersen
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha