Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease (original) (raw)
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Polskie Archiwum Medycyny Wewnetrznej-polish Archives of Internal Medicine, 2023
An increasing number of biological drugs exist, and patients have a varied response to this type of therapy. There is a need for research enabling the individualization of biological treatment based on patient's genetic predispositions. Data to date are limited and inconsistent. In our study, we analyzed selected genetic variants in the context of the deficiency of response to anti-TNF therapy in patients with Crohn's disease (CD). This work contributes to a mechanisms understanding of the lack of primary response to anti-TNF drugs in patients with CD. In addition, our study is the first pharmacogenetic research of anti-TNF therapy in Polish patients with inflammatory bowel disease. The obtained results are highly desirable, needed in clinical practice and personalized therapies, and are the basis for further research in other populations.
Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn's disease
World journal of gastroenterology, 2017
To investigate genetic factors that might help define which Crohn's disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy. This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria). 121 patie...
2020
Background & AimsPrimary non-response (PNR) to anti-tumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR.MethodsPatients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide Association Study (PheWAS).ResultsWe identified rs34767465 as associated with PNR to anti-TNF-α therapy (OR:2.07, 95%CI:1.46-2.94, p=2.43×10−7, [Replication OR:1.8, 95%CI:1.04-3.16, p=0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapM...
Anti-tumor necrosis factor (TNF) therapy is used to induce and maintain remission in Crohn’s disease (CD) patients. However, primary non-responders to initial treatment constitute 20–40% of cases. The causes of this phenomenon are still unknown. We aim to investigate the impact of the caspase 9 (CASP9) gene variants on the variable reactions of CD patients to anti-TNF therapy. The study group included 196 diagnosed and clinically characterized CD Polish patients following anti-TNF therapy. The sequence of the CASP9 gene was analyzed using next-generation and Sanger sequencing and was analyzed with the response to biological treatment. Using the RT-qPCR analysis, we estimated the CASP9 gene mRNA level in colon biopsies material from inflamed and non-inflamed tissue (21 CD patients: 14 responders and seven non-responders to anti-TNF therapy and six controls), as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from CD patients (seven responders and seven non-responders...
Effect of Anti-TNF Therapy on Mucosal Apoptosis Genes Expression in Crohn's Disease
Frontiers in Immunology, 2021
Crohn's disease (CD) is a chronic immune-mediated disorder for which there is not a fully effective treatment. Moreover, biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies leads to an effective response in only 60–70% of patients. Our previous data suggested that specific loci polymorphism of the TNFRSF1B, FCGR3A, IL1R, IL1B, and FAS genes could be a predictor of the primary non-response to anti-TNF therapy in CD patients. In this work, we propose to explain this hypothesis by functional analysis in colon biopsies and in a cell culture model. Using the RT-qPCR analysis, we estimated the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes mRNA level in colon biopsies material from inflamed and non-inflamed tissue from 21 CD patients (14 responders and 7 non-responders to anti-TNF therapy) and 6 controls, as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from 14 CD patients (seven responders and seven non-responders to anti-TN...
Contribution of TNFSF15 gene variants to Crohnʼs disease susceptibility confirmed in UK population
Inflammatory Bowel Diseases, 2008
Background: Identification of Crohn's disease (CD)-associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. Methods: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. Results: TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01-1.41) P ϭ 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR ϭ 1.44 (95% CI 1.23-1.68) P ϭ 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499-3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. Conclusions: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease-causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies.
Clinical and Experimental Immunology, 2000
Crohn's disease (CD) is a multifactorial disease with genetic heterogeneity. TNF-a plays a key role in the development of the mucosal lesions. The aim of our work was to study a single base pair polymorphism located in the promoter region of TNF gene, in a large population of CD patients with well defined phenotypes. One hundred and ninety-three patients with CD and 98 ethnically matched controls were studied. The ¹308 single base pair polymorphism of TNF gene was studied using an allele-specific polymerase chain reaction. Genotype and allelic frequencies were compared between patients and controls and between subgroups of patients defined by sex, age at diagnosis, familial history, location of disease, type of disease, extra-intestinal manifestations, and response to steroid treatment. In 29 patients a measure of TNF-a production by colonic biopsies was performed. The frequency of the allele TNF2 as well as the proportion of carriers of the allele TNF2 were slightly but not significantly lower in CD than in controls (11·9% versus 14·8% and 21·5% versus 27·6%, respectively). A more prominent difference in frequencies of allele TNF2 and in proportions of TNF2 carriers was found when comparing subgroups of patients. The frequency of allele TNF2 was significantly higher in steroid-dependent than in non-steroid-dependent disease (28·1% versus 10·3%; D ¼ 17·8%, 95% confidence interval (CI) ¼ 6·3-29·5%, P ¼ 0·0027) and tended to be higher in colonic than in small bowel disease and in fistulizing than in stricturing disease. Furthermore, TNF2 carriers tended to be more frequent in patients with steroid-dependent than non-steroid-dependent disease (43·8% versus 19·3%; D ¼ 24·5%, 95% CI ¼ 3·6-45·4%, P ¼ 0·022), in patients with fistulizing than stricturing disease (26·5% versus 9·6%; D ¼ 16·9%, 95% CI ¼ 1·1-32·6%, P ¼ 0·036), and in patients with colonic than small bowel disease (26·5% versus 11·1%; D ¼ 15·4%, 95% CI ¼ ¹0·8-31·6%, P ¼ 0·063). Finally, patients carrying at least one copy of allele 2 were found to produce slightly more TNF-a at the colonic level. The ¹308 TNF gene polymorphism may have a slight influence on the behaviour of CD. The carriage of allele 2 may favour steroid-dependent disease and to a lesser extent fistulizing and colonic disease, possibly secondary to a more intense TNF-a-driven inflammatory reaction at the mucosal level.
P372 Predicting long-term response to anti-TNFα in Crohn's disease
Journal of Crohn's and Colitis, 2012
Poster presentations was observed (p = 0.017). The wall thickness and the lumen narrowing sub-scores of SLIC showed a significant improvement compared before and after treatment (p = 0.01 and p = 0.017, respectively). Conclusions: Preliminary results suggest that SLIC and index classes may be new tools for assessing lesion variations after anti-TNFs in CD.