Format

Send to

Choose Destination
Therap Adv Gastroenterol. 2019 Sep 25;12:1756284819867848. doi: 10.1177/1756284819867848. eCollection 2019.

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

Author information

1
Gastroenterology Unit. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 62. 28006 Madrid, Spain.
2
Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
3
Gastroenterology Unit, Hospital Universitario de Fuenlabrada, Instituto de Investigación de Hospital La Paz (IdiPaz), Madrid, Spain.
4
Gastroenterology Unit, Hospital Universitario de La Fe, Valencia, Spain.
5
Gastroenterology Unit, Hospital Universitario de Galdakano, Vizcaya, Spain.
6
Gastroenterology Unit, Hospital Universitario de Donostia, Instituto Biodonostia, UPV/EHU, Ikerbasque, Guipúzcoa, Spain.
7
Gastroenterology Unit, Hospital Universitario Clínico San Carlos and IdISSC, Madrid, Spain.
8
Gastroenterology Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía/Universidad de Córdoba, Spain.
9
Gastroenterology Unit, Hospital Universitario Gregorio Marañón e IiSGM, Madrid, Spain.
10
Gastroenterology Unit, Hospital Universitario Clínico de Santiago, Santiago de Compostela, Spain.
11
Gastroenterology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
12
Gastroenterology Unit, Hospital Universitario La Paz, Madrid, Spain.
13
Universidad de Alcalá, Alcalá de Henares, Spain.
14
Gastroenterology Unit, Hospital Universitario Ramón y Cajal, Madrid, Spain.
15
Gastroenterology Unit, Hospital Universitario Alicante, Alicante, Spain.
16
Gastroenterology Unit, Hospital Clínico Universitario, Lozano Blesa, IIS Aragón, Zaragoza, Spain.
17
Gastroenterology Unit, Hospital Universitario Manises, Valencia, Spain.
18
Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Spain.

Abstract

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.

KEYWORDS:

Crohn’s disease; adalimumab; genes; infliximab; tumor necrosis factor alpha; whole-genome analysis

Conflict of interest statement

Conflict of interest statement: M Chaparro has served as a speaker, or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts Pharma. I Guerra has served as a speaker for Pfizer and Janssen and consultant and advisory member for Kern Pharma and MSD. M Iborra has received funding for educational activities, research projects and scientific meetings from Takeda and Abbvie. JL Cabriada has served as consultant for and received research funding from MSD, Abbvie, Pfizer and Kern Ph. L Bujanda: none C Taxonera has served as a speaker, a consultant and advisory member for, or has received research funding from, MSD, Abbvie, Hospira, Pfizer, Takeda, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Gebro Pharma. V García-Sánchez has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Kern Pharma, Takeda, Pfizer, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Janssen, Gebro Pharma and Otsuka Pharmaceutical. I Marín-Jiménez has served as a consultant, advisory member, speaker, or has received research funding from Abbvie, Chiesi, Faes Farma, Falk-Pharma, Ferring, Gebro Pharma, Hospira, Janssen, MSD, Otsuka Pharmaceutical, Pfizer, Shire, Takeda, Tillots, and UCB Pharma. M Barreiro-de Acosta has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen Takeda, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts Pharma, Chiesi, Gebro Pharma, Otsuka Pharmaceutical and Vifor Pharma. I Vera has served as a speaker for AbbVie, Takeda and Shire MD Martín-Arranz has served as a speaker, a consultant and advisory member for MSD; Abbvie, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceutical, Tillots Pharma and Chiesi B.Hernández-Breijo: None F.Mesonero: None L Sempere has served as a speaker, a consultant and advisory member for TAKEDA, ABBVIE, KERN, MSD Y TILLOTTS. F Gomollón has received fees for lectures from Janssen, Abbvie, Takeda, MSD and research grants (Group): MSD, Abbvie. Advisory Committees: None active at present. J Hinojosa Abbvie, MSD, Takeda, Janssen, Kern, Pfizer-Hospira, Otsuka, Faes, Ferring, Biogen, Shire. F Bermejo has served as a speaker, a consultant and advisory member for, or has received research funding from, MSD, Abbvie, Pfizer, Hospira, Takeda, Ferring, Faes Farma, Shire, Tillotts, Chiesi and Gebro. B Beltrán: None A Rodríguez Pescador JM Banales: has served as a speaker and advisory member for OWL Metabolomics. D Olivares: None P Aguilar-Melero: None L Menchén has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts and General Electric. R Ferreiro-Iglesias has received grants from Abbvie,MSD, Shire, Falk, Tillotts. I Blazquez Gomez: None B Benítez García: None LG Guijarro: None AC Marin: None D Bernardo: None JP Gisbert has served as a speaker, a consultant and advisory member for, or has received research funding from, MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma.

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center