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

Pharmacogenomics J. 2019 Dec;19(6):547-555. doi: 10.1038/s41397-019-0090-4. Epub 2019 May 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab / therapeutic use*
  • Aged, 80 and over
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal / genetics*
  • Antigens, CD / genetics*
  • Crohn Disease / drug therapy*
  • Crohn Disease / genetics*
  • Female
  • Genetic Variation / drug effects
  • Genetic Variation / genetics
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Middle Aged
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • Antigens, CD
  • CD96 antigen
  • Tumor Necrosis Factor-alpha
  • Adalimumab