IBD-linked Genetic Variance in Intestinal Transplantation A Multicenter Cohort Analysis

Abstract

Background: In solid organ transplantation, the intestine remains the most challenging. Previous studies have linked NOD2 genetic variation to intestinal transplantation (ITx) outcomes. Since then, a larger set of inflammatory bowel disease-associated genetic variants (IBDGVs) has been identified. This study aims to explore the prevalence and association of these IBDGVs with ITx outcomes. Method: Clinical data and DNA from 150 donor/recipient pairs were collected from 5 ITx centers (Leuven, Cambridge, Paris, Madrid, Buenos Aires). Genotyping-by-sequencing of 540 IBDGVs was performed, and genetic European individuals (53 donors, 101 recipients, EUR cohort) were selected. Associations between ITx outcomes [patient/graft survival and acute/chronic rejection (AR/CR)] and IBDGVs were separately analyzed if carried by the donors, the recipients, and the donor-AND-recipient using Cox regression, followed by pathway analysis (P<0.05). Results: Across all analyses (EUR cohort), multiple associations (P<0.05) were identified between IBDGVs and ITx outcomes, including 79 with AR, 34 with CR, 113 with patient survival, and 102 with graft survival. Donor/recipient IBDGVs had mixed protective (HR<1) and detrimental influences (HR>1) on outcomes, while donor-AND-recipient IBDGVs were predominantly harmful. Pathway analysis of donor-AND-recipient IBDGV-related genes showed enrichment in innate/adaptive immunity and epithelial barrier function, particularly in IL-12 and S100 family signaling, phagosome formation, and microbial pattern recognition. Upstream regulatory analysis confirmed the link to microbial sensing (31% of the genes) and antibody-mediated immune responses (20%). Conclusion: Several IBDGVs associated with ITx outcomes were identified in a multicenter genetic European cohort. These findings highlight potential markers for improving donor selection and post-transplant management.