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.
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We thank the patients and clinical specialists collaborating in the IMID Consortium for participation. We also thank Francisca Llinares-Tello (Marina Baixa Hospital, Spain) for her technical recommendations to implement the AAA-detection protocol. This study was funded by the Spanish Ministry of Economic Affairs and Competitiveness (RETOS COLABORACIÓN 2014, grant number: RTC-2014–2920–1), by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000–2006–6 and IPT-010000–2010–36), and by the “Agència de Gestió d’Ajuts Universitaris i de Recerca” (AGAUR, FI-DGR 2016, grant number: 00587), which is supported by the “Secretaria d’Universitats i Recerca” (Economy and Knowledge Department, Generalitat de Catalunya) and co-funded by the European Social Fund. The study sponsor had no role in the collection, analysis or interpretation of the data.
Conflict of interest
Dr. Panés has received consulting fees from Abbvie, Boehringer-Ingelheim, Celgene, Ferring, Genentech, GSK, Janssen, MSD, Oppilan, Pfizer, Second Genome, Roche, Takeda, Theravance and TiGenix. Speaker fees from Abbvie, Ferring, Janssen, MSD, and Takeda. Dr. 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, and Vifor Pharma. Dr. Barreiro-de Acosta has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma. The remaining authors declare that they have no conflict of interest.
Informed consent was obtained from all participants, and protocols were reviewed and approved by local institutional review boards. The present study was conducted according to the Declaration of Helsinki principles.
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Aterido, A., Palau, N., Domènech, E. et al. Genetic association between CD96 locus and immunogenicity to anti-TNF therapy in Crohn’s disease. Pharmacogenomics J 19, 547–555 (2019). https://doi.org/10.1038/s41397-019-0090-4
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