Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease

Abstract

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.

Massively parallel targeted resequencing reveals novel genetic variants associated with aspergillosis in paediatric patients with haematological malignancies

“…Conversely, two common SNPs in the TLR9 gene (promoter flanking rs187084 and rs352140 in the second exon) which showed significance for both allele and genotype frequencies (p < 0.05) in our analysis (Table II) did not reach the level of significance in an earlier association study on the risk of invasive aspergillosis among recipients of allogeneic haematopoietic cell transplants [19]. Nevertheless, many other studies have proved associations of rs187084 and rs352140 with numerous immune-related diseases, response to therapies, as well as bacterial and viral infections in populations of both Western and Eastern Eurasian ancestry [20,21,22,23,24,25]. It is also worth noting that the common rs4586 SNP, flanking the promoter of CCL2 gene, which appeared significant for genotype frequencies between our cases and controls (p = 0.0079, OR = 8.5, Table II), was recently found to be significantly correlated with anti-tumour immune reaction in Korean patients with colorectal cancer [26] and associated with the clinical outcome in Japanese individuals with locoregional gastric cancer [27].…”

Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis

“…Two SNPs in TLR2 (rs11938228 and rs4696480) with unknown function were associated with nonresponse, and this might indicate that TLR2 activity is associated with anti-TNF treatment, although the unknown function of the two SNPs makes the results difficult to interpret in a biological context. Similar associations for TLR2 (rs11938228, rs4696480) have been found when treating inflammatory bowel disease with anti-TNF, and for LY96 (rs11465996) when treating ulcerative colitis with anti-TNF, 6 supporting the notion of a possible association. Furthermore, a decrease in TLR2 levels has been found to be correlated with a decrease in PASI when treating psoriasis with anti-TNF agents 18 that could support the current findings.…”

“…We selected genes involved in nuclear factor-κB, TNF-α and pattern recognition pathways as described by Bank et al 6 and Sode et al 8 Briefly, candidates were found by searching for 'polymorphism AND Gene name AND (reporter gene OR luciferase OR ELISA OR RT-PCR OR flow cytometry OR EMSA)' and the single-nucleotide polymorphism (SNP) candidates were chosen based on the reported functionality, association with autoimmune diseases or association with response. [6][7][8] A list of all SNPs studied is presented in Supplementary Table 1a.…”

“…[6][7][8] A list of all SNPs studied is presented in Supplementary Table 1a. DNA extraction (Maxwell 16 LEV Blood DNA Kit; Promega, Madison, WI, USA) was performed as described by Bank et al…”

“…5 Pharmacogenetics has been more thoroughly investigated in inflammatory bowel disease and rheumatoid arthritis, where polymorphisms in genes encoding Toll-like receptors (TLRs) and NOD-like receptors have been found to be associated with response to anti-TNF drugs. [6][7][8][9][10] Nuclear factor-κB plays a major role in controlling inflammation and is an important regulator of pathways leading to expression of cytokines in psoriasis, including IL-1β (http://www.bu.edu/nf-kb/generesources/target-genes/). Nuclear factor-κB can be activated by TLRs and NOD-like receptors.…”