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dc.contributor.authorPREDICROHN Study Group GETECCU
dc.contributor.authorBujanda Fernández de Pierola, Luis
dc.date.accessioned2019-12-30T09:54:15Z
dc.date.available2019-12-30T09:54:15Z
dc.date.issued2019-09
dc.identifier.citationTherapeutic Advances In Gastroenterology 12 : (2019) // Article ID UNSP 1756284819867848es_ES
dc.identifier.issn1756-283X
dc.identifier.issn1756-2848
dc.identifier.urihttp://hdl.handle.net/10810/37409
dc.description.abstractBackground: 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 naive 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.es_ES
dc.description.sponsorshipThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by grants from the "Instituto de Salud Carlos III" (FIS.12/02557 and PI13/00041).es_ES
dc.language.isoenges_ES
dc.publisherSagees_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/es/*
dc.subjectadalimumabes_ES
dc.subjectCrohn's diseasees_ES
dc.subjectinfliximabes_ES
dc.subjectgeneses_ES
dc.subjecttumor necrosis factor alphaes_ES
dc.subjectwhole-genome analysises_ES
dc.subjectinflammatory bowel diseasees_ES
dc.subjectof-function variantses_ES
dc.subjectT-cellses_ES
dc.subjectinfliximabes_ES
dc.subjectgenomees_ES
dc.subjectassociationes_ES
dc.subjectstratificationes_ES
dc.subjectsusceptibilityes_ES
dc.subjectpolymorphismses_ES
dc.titleFunctional rare variants influence the clinical response to anti-TNF therapy in Crohn's diseasees_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holderCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License.es_ES
dc.rights.holderAtribución-NoComercial 3.0 España*
dc.relation.publisherversionhttps://journals.sagepub.com/doi/10.1177/1756284819867848es_ES
dc.identifier.doi10.1177/1756284819867848
dc.departamentoesMedicinaes_ES
dc.departamentoeuMedikuntzaes_ES


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Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License.
Except where otherwise noted, this item's license is described as Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License.