Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease
Chaparro, María (Instituto de Investigación Hospital Universitario de la Princesa)
Aterido, Adrià (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Guerra, Iván (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
Iborra, Marisa (Gastroenterology Unit)
Cabriada, José Luis (Hospital Universitario de Galdakano)
Bujanda, Luis (Biodonostia Osasun Ikerketako Institutura (País Basc))
Taxonera, Carlos (Hospital Clínico San Carlos (Madrid))
García-Sánchez, Valle (Universidad de Córdoba)
Marín-Jiménez, Ignacio (Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM))
Barreiro de-Acosta, Manuel (Hospital Universitario Clínico de Santiago)
Vera, Isabel (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Martín-Arranz, María Dolores (Hospital Universitario La Paz (Madrid))
Hernández-Breijo, Borja (Universidad de Alcalá)
Mesonero, Francisco (Hospital Universitario Ramón y Cajal (Madrid))
Sempere, Laura (Hospital General Universitario de Alicante (Alacant, País Valencià))
Gomollón, Fernando (Hospital Clínico Universitario "Lozano Blesa" de Zaragoza)
Hinojosa, Joaquín (Hospital de Manises (València))
Bermejo, Fernando (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
Beltrán, Belén (Gastroenterology Unit)
Rodríguez-Pescador, Ainhoa (Hospital Universitario de Galdakano)
Banales, Jesus (Biodonostia Osasun Ikerketako Institutura (País Basc))
Olivares, David (Hospital Clínico San Carlos (Madrid))
Aguilar-Melero, Patricia (Universidad de Córdoba)
Menchén, Luis (Hospital General Universitario Gregorio Marañón. Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM))
Ferreiro-Iglesias, Rocío (Hospital Universitario Clínico de Santiago)
Blázquez Gómez, Isabel (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Benitez García, Beatriz (Hospital Universitario La Paz (Madrid))
Guijarro, Luis G. (Universidad de Alcalá)
Marin, Alicia C. (Instituto de Investigación Hospital Universitario de la Princesa)
Bernardo, D (Instituto de Investigación Hospital Universitario de la Princesa)
Marsal, Sara (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Julià Cano, Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
P. Gisbert, Javier (Instituto de Investigación Hospital Universitario de la Princesa)
Universitat Autònoma de Barcelona. Departament de Medicina

Data:	2019
Resum:	Background: The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. Methods: CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. Results: A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4. 11e-4; duodenum, p = 0. 011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0. 016); damaging variants were enriched in epigenetic marks from CD8 (p = 6. 01e-4) and CD4+ (p = 0. 032) T cells. Conclusions: Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8 T cells are the main mediators of this response.
Ajuts:	Instituto de Salud Carlos III FIS.12/02557 Instituto de Salud Carlos III PI13/00041
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Therapeutic Advances in Gastroenterology, Vol. 12 (2019) , ISSN 1756-2848

DOI: 10.1177/1756284819867848
PMID: 31598133

14 p, 440.8 KB

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