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Pharmacogenomics J. 2019 May 2. doi: 10.1038/s41397-019-0090-4. [Epub ahead of print]

Genetic association between CD96 locus and immunogenicity to anti-TNF therapy in Crohn's disease.

Author information

1
Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
2
Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
3
Gastroenterology and Hepatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
4
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
5
Digestive Medicine Service, Hospital la Fe, Valencia, Spain.
6
Gastroenterology Service, Hospital General de Alicante, Alicante, Spain.
7
Digestive System Service, Hospital Clínico Universitario, Zaragoza, Spain.
8
Gastroenterology Service, Hospital Clínico San Carlos, Madrid, Spain.
9
Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
10
Gastroenterology Service, Hospital Clínico Universitario, Santiago de Compostela, Spain.
11
Gastroenterology Service, Complejo Hospitalario de León, León, Spain.
12
Gastroenterology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain.
13
Internal Medicine Service, Hospital de Cabueñes, Gijón, Spain.
14
Gastroenterology Service, Hospital Universitari Mutua de Terrassa, Barcelona, Spain.
15
Gastroenterology Department, Institut Hospital del Mar d'Investigacions Mèdiques, Institute of Research Hospital del Mar, Parc de Salut Mar, Pompeu Fabra University, Barcelona, Spain.
16
Gastroenterology Service, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.
17
Gastroenterology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
18
Digestive System Service, Universidad de Córdoba/Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, Córdoba, Spain.
19
Life Sciences Department, Barcelona Supercomputing Centre, Barcelona, Spain.
20
Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca, Spain.
21
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. javier.p.gisbert@gmail.com.
22
Gastroenterology Service, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain. javier.p.gisbert@gmail.com.
23
Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain. sara.marsal@vhir.org.

Abstract

The production of antibodies to anti-tumor necrosis factor alpha (TNF) agents is one of the main causes of treatment failure in Crohn's disease (CD). To date, however, the contribution of genetics to anti-TNF immunogenicity in CD is still unknown. The objective of the present study was to identify genetic variation associated with anti-TNF immunogenicity in CD. We performed a two-stage genome-wide association study in a cohort of 96 and 123 adalimumab-treated patients, respectively. In the discovery stage, we identified a genome-wide significant association between the CD96 locus and the production of antibodies to anti-TNF treatment (P = 1.88e-09). This association was validated in the replication stage (P < 0.05). The risk allele for anti-TNF immunogenicity was found to be also associated with a lack of response to anti-TNF therapy (P = 0.019). These findings represent an important step toward the understanding of the immunogenicity-based mechanisms that underlie anti-TNF response in CD.

PMID:
31043678
DOI:
10.1038/s41397-019-0090-4

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