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Poster presentations: Genetics 2020

P824 Molecular predictors of anti-TNF treatment response in patients with Crohn’s disease

M. WALCZAK1, L. Lykowska-Szuber2, M. Plucinska3, M. Michalak4, I. Krela-Kazmierczak2, O. Zakerska-Banaszak1, K. Stawczyk-Eder2, P. Eder2, A. Dobrowolska2, R. Slomski1, M. Skrzypczak-Zielinska1

1Institute of Human Genetics- Polish Academy of Sciences, Department of Nucleic Acid Function, Poznan, Poland, 2Poznan University of Medical Sciences, Department of Gastroenterology- Dietetics and Internal Diseases, Poznan, Poland, 3Institute of Molecular Biology and Biotechnology- Faculty of Biology- Adam Mickiewicz University, Department of Computational Biology, Poznan, Poland, 4Poznan University of Medical Sciences, Department of Computer Sciences and Statistics, Poznan, Poland

Background

Anti-tumour necrosis factor (anti-TNF) therapy has revolutionised the treatment of Crohn’s disease (CD). These drugs induce clinical and mucosal remission with high effectiveness, however almost 20–40% of patients do not respond to initial treatment. The exact mechanism of primary non-response is still unknown. The aim of the study was to investigate the impact of genetic interindividual differences on patients’ response. This will allow to identify molecular predictors of variable reaction to anti-TNF treatment.

Methods

DNA samples were obtained from 107 diagnosed and clinically characterised CD patients following anti-TNF therapy, where 12 of patients were classified as nonresponders. Based on long-range PCR libraries and next-generation sequencing (NGS), a panel of 23 genes belonging to TNF superfamily, proinflammatory factors, apoptosis-related proteins, signal transmission factors and receptors was analysed. After NGS, bioinformatical and statistical analysis were performed.

Results

In total, 598 single-nucleotide variants (SNP) for all analysed targets were identified. Patients’ nonresponse was associated with genotypes in 12 following loci (p ≤ 0.05): rs1061624 (OR: 4.22; 95% CI: 1.33–13.34) in TNFRSF1B gene, rs7896789 (OR: 0.27; 95% CI: 0.09–0.78) in FAS gene, rs2041747 (OR: 0.17; 95% CI: 0.04–0.80) in IL1R gene, rs373184583 (OR: 0.29; 95% CI: 0.09–0.82), rs12128686 (OR: 0.29; 95% CI: 0.09–0.82), rs7539036 (OR: 0.31; 95% CI: 0.11–0.87) and rs6672453 (OR: 0.31; 95% CI: 0.11–0.87) in FCGR3A gene, rs1071676 (OR: 2.47; 95% CI: 1.04–5.85), rs1143639 (OR: 2.47; 95% CI: 1.04–5.85), rs1143637 (OR: 2.47; 95% CI: 1.04–5.85) and rs1143634 (OR: 2.47; 95% CI: 1.04–5.85) in IL1B gene as well as rs55790676 (OR: 2.64; 95% CI: 1.02–6.83) in ADAM17 gene.

Conclusion

Obtained results suggest that molecular changes in genes involved in TNF activity may play an important role in response to anti-TNF treatment and be useful as molecular markers indicating potential patients’ response. Additionally, these results may contribute to better understanding the mechanism of monoclonal antibodies action in IBD treatment.