Variants of the CASP9 gene as candidate markers for primary response to anti-TNF therapy in Crohn's disease patients

J Appl Genet. 2023 Dec;64(4):759-768. doi: 10.1007/s13353-023-00783-7. Epub 2023 Sep 2.


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 to anti-TNF therapy) and eight controls. Our findings indicated association of variants rs1052571 and rs4645978 with response to anti-TNF monoclonal antibodies (mAbs). Moreover, we observed tendency for reduced expression after incubation with anti-TNF in the group of CD patients, in contrast to the control group. Our results suggest that response to anti-TNF therapy in CD patients may be an effect of variants of the CASP9 gene as a key effector of the internal pathway of apoptosis; however, further population and functional research are necessary.

Keywords: Anti-TNF mAbs; Biological therapy; CASP9 gene; Crohn’s disease; Response.

MeSH terms

  • Apoptosis
  • Caspase 9 / genetics
  • Caspase 9 / metabolism
  • Crohn Disease* / drug therapy
  • Crohn Disease* / genetics
  • Humans
  • Infliximab / metabolism
  • Infliximab / therapeutic use
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Tumor Necrosis Factor Inhibitors


  • Infliximab
  • Tumor Necrosis Factor Inhibitors
  • CASP9 protein, human
  • Caspase 9