Novel aspects in the genetics of celiac diseasecopy number variation, methylation and coregulation in nfkb-related genes

  1. FERNANDEZ JIMENEZ, NORA
Dirigida por:
  1. José Ramón Bilbao Catalá Director

Universidad de defensa: Universidad del País Vasco - Euskal Herriko Unibertsitatea

Fecha de defensa: 28 de febrero de 2014

Tribunal:
  1. Ana María Zubiaga Elordieta Presidente/a
  2. Luis Castaño González Secretario
  3. Luigi Greco Vocal
  4. Eduardo Arranz Sanz Vocal
  5. Rosa Miró Ametller Vocal

Tipo: Tesis

Teseo: 116487 DIALNET

Resumen

Celiac disease (CD) is a chronic autoimmune disease with a high prevalence. A better understanding of the natural history of the disease could allow us to identify therapeutic targets that although will never be an alternative to the gluten-free diet (GFD), could help palliating the acute symptoms of an accidental or occasional transgression of the treatment. The thesis tries to unravel the genetic complexity of the NF¿B route, through novel approaches including copy number variation, methylation and gene coregulation analyses. We have demonstrated that copy number variation at the ß-defensin gene cluster is associated with CD susceptibility. We have compared quantitave PCR (qPCR) and Paralog Ratio Test (PRT) to assess copy number variation, finding that although qPCR is more sensititive to input DNA normalization, PRT is more affected by DNA degradation. Additionally, the thesis identifies several NF¿B-related genes that are constitutively upregulated in CD as part of the pathway core, while those specifically upregulated in active disease are more peripheral to the route. Using in vitro culture and challenge of human tissue, we have tested MALT1 as a putative therapeutic target for acute symptoms of disease. Finally, we have also studied the role of DNA methylation in CD, finding several differences among CD patients and healthy controls, with several genes exclusively co-methylated in CD.