Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease

Artículo escrito por un elevado número de autores, sólo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiera, y los autores pertenecientes a la UAM

Detalles Bibliográficos
Autores: Chaparro Sánchez, María, Marín, Alicia C., Bernardo, David, Pérez Gisbert, Francisco Javier, PREDICROHN Study Group
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/690782
Acceso en línea:http://hdl.handle.net/10486/690782
https://dx.doi.org/10.1177/1756284819867848
Access Level:acceso abierto
Palabra clave:adalimumab
Crohn’s disease
infliximab
genes
tumor necrosis factor alpha
whole-genome analysis
Medicina
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spelling Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s diseaseChaparro Sánchez, MaríaMarín, Alicia C.Bernardo, DavidPérez Gisbert, Francisco JavierPREDICROHN Study GroupadalimumabCrohn’s diseaseinfliximabgenestumor necrosis factor alphawhole-genome analysisMedicinaArtículo escrito por un elevado número de autores, sólo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiera, y los autores pertenecientes a la UAMThe 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 responseThis research was funded by grants from the “Instituto de Salud Carlos III” (FIS.12/02557 and PI13/00041)SAGE PublicationsDepartamento de MedicinaFacultad de Medicina20192019-09-25research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/690782https://dx.doi.org/10.1177/1756284819867848reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6907822026-06-23T12:46:27Z
dc.title.none.fl_str_mv Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
title Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
spellingShingle Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
Chaparro Sánchez, María
adalimumab
Crohn’s disease
infliximab
genes
tumor necrosis factor alpha
whole-genome analysis
Medicina
title_short Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
title_full Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
title_fullStr Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
title_full_unstemmed Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
title_sort Functional rare variants influence the clinical response to anti-TNF therapy in Crohn’s disease
dc.creator.none.fl_str_mv Chaparro Sánchez, María
Marín, Alicia C.
Bernardo, David
Pérez Gisbert, Francisco Javier
PREDICROHN Study Group
author Chaparro Sánchez, María
author_facet Chaparro Sánchez, María
Marín, Alicia C.
Bernardo, David
Pérez Gisbert, Francisco Javier
PREDICROHN Study Group
author_role author
author2 Marín, Alicia C.
Bernardo, David
Pérez Gisbert, Francisco Javier
PREDICROHN Study Group
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Medicina
Facultad de Medicina
dc.subject.none.fl_str_mv adalimumab
Crohn’s disease
infliximab
genes
tumor necrosis factor alpha
whole-genome analysis
Medicina
topic adalimumab
Crohn’s disease
infliximab
genes
tumor necrosis factor alpha
whole-genome analysis
Medicina
description Artículo escrito por un elevado número de autores, sólo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiera, y los autores pertenecientes a la UAM
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-09-25
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/690782
https://dx.doi.org/10.1177/1756284819867848
url http://hdl.handle.net/10486/690782
https://dx.doi.org/10.1177/1756284819867848
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv SAGE Publications
publisher.none.fl_str_mv SAGE Publications
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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