Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

The Pharmacogenomics Journal volume 19, pages 547–555 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015;12:720–7.

    Article  Google Scholar 

  2. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.

    Article  CAS  Google Scholar 

  3. Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40:443–8.

    Article  Google Scholar 

  4. Berns M, Hommes DW. Anti-TNF-alpha therapies for the treatment of Crohn’s disease: the past, present and future. Expert Opin Invest Drugs. 2016;25:129–43.

    Article  CAS  Google Scholar 

  5. Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760–7.

    CAS  PubMed  Google Scholar 

  6. Atzeni F, Talotta R, Salaffi F, Cassinotti A, Varisco V, Battellino M, et al. Immunogenicity and autoimmunity during anti-TNF therapy. Autoimmun Rev. 2013;12:703–8. https://doi.org/10.1016/j.autrev.2012.10.021.

    Article  CAS  PubMed  Google Scholar 

  7. Chaparro M, Guerra I, Munoz-Linares P, Gisbert JP. Systematic review: antibodies and anti-TNF-alpha levels in inflammatory bowel disease. Aliment Pharm Ther. 2012;35:971–86.

    Article  CAS  Google Scholar 

  8. Paul S, Moreau AC, Del Tedesco E, Rinaudo M, Phelip JM, Genin C., et al. Pharmacokinetics of adalimumab in inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20:1288–95. 0.097/MIB.0000000000000037.

    Article  Google Scholar 

  9. Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, et al. Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn’s disease. Aliment Pharm Ther. 2014;39:1349–62.

    Article  CAS  Google Scholar 

  10. Hyams JS, Griffiths A, Markowitz J, Baldassano RN, Faubion WA Jr., Colletti RB, et al. Safety and efficacy of adalimumab for moderate to severe Crohn’s disease in children. Gastroenterology. 2012;143:365–74.e2. https://doi.org/10.1053/j.gastro.2012.04.046.

    Article  CAS  PubMed  Google Scholar 

  11. Roblin X, Marotte H, Rinaudo M, Del Tedesco E, Moreau A, Phelip JM, et al. Association between pharmacokinetics of adalimumab and mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2014;12:80–4.e2. https://doi.org/10.1016/j.cgh.2013.07.010.

    Article  CAS  PubMed  Google Scholar 

  12. Mazor Y, Almog R, Kopylov U, Ben Hur D, Blatt A, Dahan A., et al. Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn’s disease. Aliment Pharm Ther. 2014;40:620–8. https://doi.org/10.1111/apt.12869.

    Article  CAS  Google Scholar 

  13. West RL, Zelinkova Z, Wolbink GJ, Kuipers EJ, Stokkers PC, van der Woude CJ. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharm Ther. 2008;28:1122–6. 10.11/j.365-2036.08.03828.x.

    Article  CAS  Google Scholar 

  14. Hemmer B, Stuve O, Kieseier B, Schellekens H, Hartung HP. Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis. Lancet Neurol. 2005;4:403–12.

    Article  CAS  Google Scholar 

  15. Magdelaine-Beuzelin C, Vermeire S, Goodall M, Baert F, Noman M, Assche GV, et al. IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab. Pharm Genom. 2009;19:383–7.

    Article  CAS  Google Scholar 

  16. Bartelds GM, Wijbrandts CA, Nurmohamed MT, Wolbink GJ, de Vries N, Tak PP, et al. Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms. Arthritis Rheum. 2009;60:2541–2.

    Article  CAS  Google Scholar 

  17. Julia A, Tortosa R, Hernanz JM, Canete JD, Fonseca E, Ferrandiz C, et al. Risk variants for psoriasis vulgaris in a large case-control collection and association with clinical subphenotypes. Hum Mol Genet. 2012;21:4549–57.

    Article  CAS  Google Scholar 

  18. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6. discussion16-9

    Article  CAS  Google Scholar 

  19. Llinares-Tello F, Rosas-Gomez de Salazar J, Senabre-Gallego JM, Santos-Soler G, Santos-Ramirez C, Salas-Heredia E, et al. Practical application of acid dissociation in monitoring patients treated with adalimumab. Rheuma Int. 2014;34:1701–8.

    Article  CAS  Google Scholar 

  20. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  CAS  Google Scholar 

  21. Aterido A, Julia A, Ferrandiz C, Puig L, Fonseca E, Fernandez-Lopez E, et al. Genome-wide pathway analysis identifies genetic pathways associated with psoriasis. J Invest Dermatol. 2016;136:593–602.

    Article  CAS  Google Scholar 

  22. Tian C, Gregersen PK, Seldin MF. Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet. 2008;17:R143–50.

    Article  CAS  Google Scholar 

  23. Price AL, Zaitlen NA, Reich D, Patterson N. New approaches to population stratification in genome-wide association studies. Nat Rev Genet. 2010;11:459–63.

    Article  CAS  Google Scholar 

  24. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–9.

    Article  CAS  Google Scholar 

  25. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1:514.

    Article  CAS  Google Scholar 

  26. Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Doi S, et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet. 2011;43:893–6.

    Article  CAS  Google Scholar 

  27. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet. 2009;41:1303–7.

    Article  CAS  Google Scholar 

  28. Clarke GM, Anderson CA, Pettersson FH, Cardon LR, Morris AP, Zondervan KT. Basic statistical analysis in genetic case-control studies. Nat Protoc. 2011;6:121–33.

    Article  CAS  Google Scholar 

  29. Kugler KG, Mueller LA, Graber A. MADAM - an open source meta-analysis toolbox for R and Bioconductor. Source Code Biol Med. 2010;5:3.

    Article  Google Scholar 

  30. Ihaka R, Gentleman GR. R: a language for data analysis and graphics. J Comput Graph Stat. 1996;5:299–314.

    Google Scholar 

  31. Wang PL, O’Farrell S, Clayberger C, Krensky AM. Identification and molecular cloning of tactile. A novel human T cell activation antigen that is a member of the Ig gene superfamily. J Immunol. 1992;148:2600–8.

    CAS  PubMed  Google Scholar 

  32. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al.The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580-5.

  33. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15:243–54.

    Article  CAS  Google Scholar 

  34. Chan CJ, Martinet L, Gilfillan S, Souza-Fonseca-Guimaraes F, Chow MT, Town L, et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat Immunol. 2014;15:431–8.

    Article  CAS  Google Scholar 

  35. Haralambieva IH, Lambert ND, Ovsyannikova IG, Kennedy RB, Larrabee BR, Pankratz VS, et al. Associations between single nucleotide polymorphisms in cellular viral receptors and attachment factor-related genes and humoral immunity to rubella vaccination. PLoS ONE. 2014;9:e99997.

    Article  Google Scholar 

  36. Ovsyannikova IG, Salk HM, Larrabee BR, Pankratz VS, Poland GA. Single nucleotide polymorphisms/haplotypes associated with multiple rubella-specific immune response outcomes post-MMR immunization in healthy children. Immunogenetics. 2015;67:547–61.

    Article  CAS  Google Scholar 

  37. Maier MK, Seth S, Czeloth N, Qiu Q, Ravens I, Kremmer E, et al. The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens. Eur J Immunol. 2007;37:2214–25.

    Article  CAS  Google Scholar 

  38. Kamran N, Takai Y, Miyoshi J, Biswas SK, Wong JS, Gasser S. Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigen-presenting cells. PLoS ONE. 2013;8:e54406.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Adrià Aterido, Núria Palau

Authors and Affiliations

  1. Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain

    Adrià Aterido, Núria Palau, María López-Lasanta, Andrea Pluma, Sara Marsal & Antonio Julià

  2. Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Adrià Aterido

  3. Gastroenterology and Hepatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

    Eugeni Domènech & Josep Manyé

  4. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain

    Eugeni Domènech, Pilar Nos Mateu, Ana Gutiérrez, Fernando Gomollón, Maria Esteve, María Chaparro, Julián Panés & Javier P. Gisbert

  5. Digestive Medicine Service, Hospital la Fe, Valencia, Spain

    Pilar Nos Mateu

  6. Gastroenterology Service, Hospital General de Alicante, Alicante, Spain

    Ana Gutiérrez

  7. Digestive System Service, Hospital Clínico Universitario, Zaragoza, Spain

    Fernando Gomollón

  8. Gastroenterology Service, Hospital Clínico San Carlos, Madrid, Spain

    Juan L. Mendoza

  9. Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Esther Garcia-Planella

  10. Gastroenterology Service, Hospital Clínico Universitario, Santiago de Compostela, Spain

    Manuel Barreiro-de Acosta

  11. Gastroenterology Service, Complejo Hospitalario de León, León, Spain

    Fernando Muñoz

  12. Gastroenterology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain

    Maribel Vera

  13. Internal Medicine Service, Hospital de Cabueñes, Gijón, Spain

    Cristina Saro

  14. Gastroenterology Service, Hospital Universitari Mutua de Terrassa, Barcelona, Spain

    Maria Esteve

  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

    Montserrat Andreu

  16. Gastroenterology Service, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain

    María Chaparro & Javier P. Gisbert

  17. Gastroenterology Department, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

    Julián Panés

  18. Digestive System Service, Universidad de Córdoba/Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, Córdoba, Spain

    Valle García-Sánchez

  19. Life Sciences Department, Barcelona Supercomputing Centre, Barcelona, Spain

    Laia Codó

  20. Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca, Spain

    Andrés García-Montero

Authors
  1. Adrià Aterido
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Núria Palau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eugeni Domènech
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pilar Nos Mateu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Gutiérrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fernando Gomollón
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan L. Mendoza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Esther Garcia-Planella
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Manuel Barreiro-de Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fernando Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maribel Vera
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Cristina Saro
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maria Esteve
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Montserrat Andreu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. María Chaparro
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Julián Panés
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Valle García-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. María López-Lasanta
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Andrea Pluma
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Laia Codó
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Andrés García-Montero
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Josep Manyé
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Javier P. Gisbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Sara Marsal
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Antonio Julià
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Javier P. Gisbert or Sara Marsal.

Ethics declarations

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.

Ethics statement

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-019-0090-4

Search

Advanced search

Quick links