Bank S, Andersen P S, Burisch J, Pedersen N, Roug S, Galsgaard J, Turino S Y, Brodersen J B, Rashid S, Rasmussen B K, Avlund S, Olesen T B, Hoffmann H J, Thomsen M K, Thomsen V Ø, Frydenberg M, Nexø B A, Sode J, Vogel U, Andersen V
1] Medical Department, Viborg Regional Hospital, Viborg, Denmark [2] Biomedicine, University of Aarhus, Aarhus, Denmark.
Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
Pharmacogenomics J. 2014 Dec;14(6):526-34. doi: 10.1038/tpj.2014.19. Epub 2014 Apr 29.
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.
抗肿瘤坏死因子-α（TNF-α）用于治疗炎症性肠病（IBD）的重症病例，包括克罗恩病（CD）和溃疡性结肠炎（UC）。然而，三分之一的患者对该治疗无反应。基因标志物可能预测个体对抗TNF治疗的反应。采用候选基因方法，在738例既往未接受过抗TNF治疗的丹麦IBD患者中，评估了26个调节炎症的基因中的39个主要功能性单核苷酸多态性（SNP）。使用逻辑回归（粗分析以及校正年龄、性别和吸烟状况后的分析）对结果进行分析。19个改变NFκB介导的炎症反应的功能性多态性（TLR2（rs3804099、rs11938228、rs1816702、rs4696480）、TLR4（rs5030728、rs1554973）、TLR9（rs187084、rs3
