MADCAM1 Gene Variants as Potential Pharmacogenomics Markers for Vedolizumab Response in Crohn's Disease Bio-Naïve Patients.

Background/Objectives. Crohn's disease (CD) is a chronic immune-mediated inflammatory disease that affects the gastrointestinal tract. The management of CD is complex, and treatment requires numerous therapies. One of the best gut-selective biologic drugs with proven efficacy in induction and maintenance therapy in patients with CD is vedolizumab (VDZ). Nevertheless, not all patients with CD respond to VDZ treatment, possibly due to their individual pharmacogenomic profiles. In this study, the association of variants in genes encoding molecules involved in biological pathways targeted by VDZ, ITGA4, ITGB7, and MADCAM1, with VDZ response was analyzed. In addition, Human Leukocyte Antigen (HLA) alleles were investigated. Methods. Whole exome sequencing was performed on 63 CD patients treated with VDZ as first-line biologic therapy. Genetic variants were associated with response to VDZ treatment, estimated as follows: (1) good clinical response (patients assigned to standard maintenance protocol after 14-week induction) or partial (patients assigned to optimized maintenance protocol after 14-week induction); (2) good biochemical response (CRP ≤ 10 mg/L at week 14) or poor (CRP > 10 mg/L at week 14). Results. Two MADCAM1 variants were associated with VDZ response, as defined by CRP values in week 14 of VDZ therapy. The genetic variant MADCAM1 rs758941486 was associated with poor CRP reduction in response to VDZ induction therapy, while MADCAM1 rs1555716175 was associated with optimal CRP reduction. Anti-drug antibody-related HLA-DRB1, DQB1, and DQA1 alleles were not associated with VDZ response. Conclusions. This is a pioneering pharmacogenomics study on the VDZ direct therapeutic targets in bio-naïve CD patients, which opens the door for future research.