According to the results of a study published in Blood Advances, a genetic variant in the glucokinase regulator (GCKR) gene that was previously associated with inflammatory bowel disease (IBD) is also associated with the risk of moderate to severe gut graft vs host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT).

Given the overlap in clinical manifestations, pathogenic mechanisms, and genetic risk factors between steroid-refractory acute GVHD and IBD, the investigators hypothesized that genetic variants associated with IBD may also be associated with the risk of moderate to severe gut GVHD after HCT.

The researchers leveraged a comprehensive list of genetic regions containing 296 single nucleotide polymorphisms (SNPs) and 26 HLA alleles associated with IBD that was compiled by the International IBD Genetics Consortium (IIBDGC).


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All patients (3274) included in the study were of European ancestry and had a first allogeneic HCT (with HLA-matched related or unrelated donors) at the Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance between 1990 and 2011. Associations of the candidate variants with gut GVHD were first tested in a discovery (n=1980) cohort. Then, variants with significant associations in the discovery cohort were tested independently in a replication cohort (n=1294).

Among all SNPs and HLA alleles tested, the investigators found that a single SNP (rs1260326, homozygous T allele) in the GCKR gene was associated with a higher risk of stage 2-4 gut GVHD among patients in both cohorts.

Because GCKR is expressed primarily in the liver, the authors speculated that it may be unlikely to account for the association with IBD or stage 2-4 gut GVHD. However, they noted that the variant is located within a larger IBD-associated region of the genome that has biological plausibility and contains another variant (rs4665972) that has a strong nonrandom association with rs1260326.

“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,” the authors wrote. “Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.”

The major limitations of the study included that the study cohort was of European ancestry only and had a relatively small sample size relative to the IIBDGC cohort (about 38,000), which may have caused relevant IBD-associated variants to be missed in this analysis of stage 2-4 gut GVHD.

Reference

Martin PJ, Storer BE, Levine DM, Hansen JA. Genetic variants associated with inflammatory bowel disease and gut graft-versus-host disease. Blood Adv. Published online September 17, 2021. doi:10.1182/bloodadvances.2021004959