Genetic Risk Factors for Sclerotic Graft-Versus-Host Disease

Background: Sclerotic graft-versus-host disease (GVHD) is a distinctive phenotype of chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), characterized by fibrosis of the skin or fascia, and often associated with severe disability and morbidity. Sclerotic GVHD has clinical and histopathological similarities with systemic sclerosis, an autoimmune disease whose risk is influenced by genetic polymorphisms.

Patients and methods: We identified 15 candidate single-nucleotide polymorphisms (SNPs) that have well-documented association with susceptibility to systemic sclerosis. We hypothesized that these SNPs would also have associations with risk of sclerotic GVHD if the two diseases have similar pathogenic mechanisms. We evaluated the candidate SNPs for association with the sclerotic phenotype in a cohort of 891 patients who were diagnosed with chronic GVHD and had recipient or donor samples available for genotyping. The candidate SNPs were located in BANK1, BLK, CD247, HLA-DRA, HLA-DQB1, HLA-DPA1, IL12RB2, IRF8, PTPN22, STAT4, TNFSF4, TNIP1 and TNPO3-IRF5. Genotyping assays used the Affymetrix 5.0 Human GeneChip and Illumina 1M Quad and Illumina 2.5M BeadArrays. Candidate SNPs not genotyped on the array were imputed using the 1000 Genomes Project Phase 1 SNPs as a reference panel. Cox regression models were used to examine associations of donor and recipient SNPs with risk of sclerotic GVHD. Each SNP was assessed for allelic (additive) and genotypic (dominant and recessive) models. A two-sided P-value of <0.05 was considered statistically significant.

Results: Three of the candidate SNPs were associated with risk of sclerotic GVHD (Table): rs10516487 (BANK1: B-cell scaffold protein with ankyrin repeats 1), rs2056626 (CD247: T-cell receptor zeta subunit) and rs987870 (HLA-DPA1). Despite adequate power to detect associations, candidate SNPs in HLA-DRA and HLA-DQB1 did not show statistically significant associations with risk of sclerotic GVHD. Results for r987870 motivated further exploration of the association between HLA-DP and the risk of sclerotic GVHD. HLA-DP molecules have a P1 peptide-presentation pocket defined by M (methionine) or Q (glutamine) at position 31 of the DP alpha chain and by EAV (glutamic acid-alanine-valine) or GPM (glycine-proline-methionine) motifs at positions 85-87 of the DP beta chain. The risk of sclerotic GVHD was decreased in patients who had HLA-DP molecules with a Q~GPM pocket (HR 0.55, 95% CI 0.38-0.80, P=0.002).

Conclusion: These results suggest similarities in the mechanisms that cause sclerotic GVHD and systemic sclerosis, and indicate a critical role of the adaptive immune system, including B cells, T cells, and HLA-DP-mediated antigen presentation in the pathogenic mechanisms of both sclerotic GVHD and systemic sclerosis. Genetic variation can modify the immune pathology and significantly alter the disease phenotype of chronic GVHD after HCT.