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

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.

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium

“…Although the association of the NFKB2 rs1056890 SNP with IL10 levels neither survive correction for multiple testing, our results were in agreement with previous studies demonstrating that NFKB2 unlikely NFKB1 is implicated in the control of antigen presenting cell function and not in the activation of T and B cells. Likewise, recent studies have also identified genetic polymorphisms within the NFKB pathway as genetic biomarkers for response to TNFi in RA 42 but also other autoimmune diseases 42 , which further supported our hypothesis suggesting a key role of the NFKB2 gene in modulating the response to TNFi. In addition, in silico tools such as Regulome showed that the rs1056890 SNP has a score of 4, which means that this polymorphism could affect transcription factor affinity and DNase peak 43 .…”

<p>Integrated Gene Expression Profiling Analysis Reveals Probable Molecular Mechanism and Candidate Biomarker in Anti-TNFα Non-Response IBD Patients</p>

“…Almost all DEGs involved in the Toll-like signaling pathway were up-regulated, which was consistent with the recent study found that polymorphisms of TLR pathway are valuable significant predictors for the response to anti-TNFα therapy among patients with autoimmune disease. 50,51 Firstly, as motioned above, TLR pathway facility the production of lgG and thereby stimulate the FcγR signal. Secondly, FcγR stimulates phagocytosis.…”

Smart Model to Distinguish Crohn’s Disease from Ulcerative Colitis

“…There are many logistic models that show the relationship between IBD varieties [26][27][28][29][30][31]. However, the most accurate model which could clearly point the appropriate group for the patient has not been found so far.…”