Genetic variants associated with inflammatory bowel disease and gut graft-versus-host disease

Key Points An IBD-associated locus tagged by rs1260326 is associated with gut GVHD after allogeneic HCT.Genetic variation in anti-inflammatory activity mediated by FNDC4 within this locus could account for the association with gut GVHD.
Visual Abstract
Previous studies have identified genetic variants associated with inflammatory bowel disease (IBD). We tested the hypothesis that some of these variants are also associated with the risk of moderate to severe gut graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Associations were evaluated initially in a discovery cohort of 1980 HCT recipients of European ancestry with HLA-matched related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1294 HCT recipients. Among the 296 single-nucleotide polymorphisms and 26 HLA alleles tested, we found that the recipient rs1260326 homozygous T allele in GCKR was associated with a higher risk of stage 2 to 4 gut GVHD. No other candidate variants were associated with stage 2 to 4 gut GVHD. The rs1260326 variant resides in an IBD-associated locus containing FNDC4, a gene that encodes a secreted anti-inflammatory factor that dampens macrophage activity and improves colitis in mice. Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.