Abstract
Anti-tumor necrosis factor (TNF) therapy is used for the induction and maintenance of remission in Crohn’s disease (CD) patients. However, primary nonresponders to initial treatment constitute 20%–40% of cases. The causes of this phenomenon are still unknown. In this study, we aimed to determine the genetic predictors of the variable reactions of CD patients to anti-TNF therapy. Using long-range PCR libraries and the next-generation sequencing (NGS) method, we performed broad pharmacogenetic studies including a panel of 23 genes (TNFRSF1A, TNFRSF1B, CASP9, FCGR3A, LTA, TNF, FAS, ADAM17, IL17A, IL6, MMP1, MMP3, S100A8, S100A9, S100A12, TLR2, TLR4, TLR9, CD14, IL23R, IL23, IL1R, and IL1B) in a group of 107 diagnosed and clinically characterized CD patients following anti-TNF therapy. In the studied group, we indicated, in total, 598 single nucleotide variants for all analyzed genomic targets. Twelve patients (11.2%) did not respond to the induction therapy, which was associated with alleles in 11 loci located in FCGR3A (rs7539036, rs6672453, rs373184583, and rs12128686), IL1R (rs2041747), TNFRSF1B (rs5746053), IL1B (rs1071676, rs1143639, rs1143637, and rs1143634), and FAS (rs7896789) genes. After multiple comparison corrections, the results were not statistically significant, however for nonresponders the alleles distribution for those loci presented large differences and specified scheme compared to responders and populations. These findings require further investigation in an independent larger cohort before introducing them for a clinical setting, however, we identified an interesting direction. Polymorphism of the FCGR3A, IL1R, TNFRSF1B, IL1B, and FAS genes could be a predictor of the primary response to anti-TNF therapy in CD patients.
Highlights
The use of anti-tumor necrosis factor agents has revolutionized the treatment of inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD)
In the group of responders, the values of all four parameters used in CD monitoring: Crohn’s Disease Activity Index (CDAI), CRP, SES-CD, and SEAS-CD after induction therapy decreased significantly compared to the state before therapy (p < 0.0001)
By using nextgeneration sequencing (NGS) combined with LR-PCR libraries, we attempted to determine genetic predictors and share our conclusions of investigating a cohort of 107 Polish IBD patients treated with anti-tumor necrosis factor (TNF) agents who presented various responses to the therapy
Summary
The use of anti-tumor necrosis factor (anti-TNF) agents has revolutionized the treatment of inflammatory bowel diseases (IBDs), which include Crohn’s disease (CD). These drugs induce clinical and mucosal remission, as well as modify the natural course of the disease. Much attention has been paid to the pharmacokinetics of biological drugs, which undoubtedly play a role in the long-term response It seems that other mechanisms are involved in the induction phase, including genetic conditions, whereas drug pharmacokinetics is a secondary phenomenon (Drabik et al, 2016; Yamamoto-Furusho, 2017; Linares-Pineda et al, 2018). The regulation of the apoptosis of intestinal inflammatory cells and the regulation of selected inflammation are of vital importance (Itoh et al, 2001; Atreya et al, 2011)
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