The Genetic Diversity and Dysfunctionality of Catalase Associated with a Worse Outcome in Crohn’s Disease

Autores de IIS La Fe

• Marisa Iborra Colomino

  Autor

• Inés Moret Tatay

  Autor

• 

  Pilar Nos Mateu

  Autor

• Belén Beltrán Niclós

  Autor

Participantes ajenos a IIS La Fe

• Busó E.
• García-Giménez J.L.
• Ricart E.
• Gisbert J.P.
• Cabré E.
• Esteve M.
• Márquez-Mosquera L.
• García-Planella E.
• Guardiola J.
• Pallardó F.V.
• Serena C.
• Algaba-Chueca F.
• Domenech E.

Grupos

• Enfermedad Inflamatoria Intestinal

Abstract

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression. © 2022 by the authors.

Keywords

• Antioxidants; Case-Control Studies; Catalase; Crohn Disease; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Inflammation; Polymorphism, Single Nucleotide; Retrospective Studies; actb 6 protein; adalimumab; alkaline phosphatase; alpha actin; azathioprine; catalase; complementary DNA; corticosteroid; DNA polymerase; fibrinogen; genomic DNA; glyceraldehyde 3 phosphate dehydrogenase; hmbs 7 protein; infliximab; mesalazine; phosphoprotein phosphatase 2A; protein kinase C zeta; unclassified drug; antioxidant; catalase; adult; Article; clinical outcome; cohort analysis; concentration process; controlled study; Crohn disease; disease association; female; gene expression; genetic association; genetic transcription; genetic variability; genotype; human; human cell; inflammatory bowel disease; long term care; major clinical study; male; middle aged; oxidative stress; peripheral blood mononuclear cell; peripheral white mononuclear cell; population; protein expression; regu