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

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.

SUBMITTER: Martin PJ

PROVIDER: S-EPMC8579259 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Martin Paul J PJ Storer Barry E BE Levine David M DM Hansen John A JA

Blood advances 20211101 21

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 t ...[more]

PMID: 34535014

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Project description:Taxonomic composition of the gut microbiota at the time of neutrophil engraftment is associated with the development of acute gastrointestinal graft-versus-host disease (GI GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation. However, less is known about the relationship between the gut microbiota and development of steroid-refractory GI GVHD immediately before the onset of disease. Markers of steroid-refractory GI GVHD are needed to identify patients who may benefit from the early initiation of non-corticosteroid-based GVHD treatment. Our aim was to identify differences in taxonomic composition in stool samples from patients without GVHD, with steroid-responsive GVHD and with steroid-refractory GI GVHD to identify predictive microbiome biomarkers of steroid-refractory GI GVHD. We conducted a retrospective case-control, single institution study, performing shotgun metagenomic sequencing on stool samples from patients with (n = 36) and without GVHD (n = 34) matched for time since transplantation. We compared the taxonomic composition of the gut microbiome in those with steroid-sensitive GI GVHD (n = 17) and steroid-refractory GI GVHD (n = 19) to each other and to those without GVHD. We also performed associations between steroid-refractory GI GVHD, gut taxonomic composition, and fecal calprotectin, a marker of GI GVHD to develop composite fecal markers of steroid-refractory GVHD before the onset of GI disease. We found that fecal samples within 30 days of GVHD onset from patients with and without GVHD or with and without steroid-refractory GI GVHD did not differ significantly in Shannon diversity (alpha-diversity) or in overall taxonomic composition (beta-diversity). Although those patients without GVHD had higher relative abundance of Clostridium spp., those with and without steroid-refractory GI GVHD did not significantly differ in taxonomic composition between one another. In our study, fecal calprotectin before disease onset was significantly higher in patients with GVHD compared to those without GVHD and higher in patients with steroid-refractory GI GVHD compared to steroid-sensitive GI GVHD. No taxa were significantly associated with higher levels of calprotectin.

Dataset Information

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

Publications

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

Similar Datasets

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