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P722 Clinical and genetic characterisation of patients with graft-vs-host disease after allogeneic hematopoietic cell transplantation suggests a role for JAK2, IL2RA, and HLA-DRB1

S. van Sommeren*1, H. M. de Jonge1, J. Kuball2, L. te Boome2, E. Vellenga3, G. Huls3, R. Weersma1

1University Medical Centre Groningen, Department of Gastroenterology and Hepatology MDL BB41, Groningen, Netherlands, 2University Medical Centre Utrecht, Haematology, Utrecht, Netherlands, 3University Medical Centre Groningen, Haematology, Groningen, Netherlands


Allogeneic hematopoietic cell transplantation (HCT) is the most effective tumour immunotherapy available for a variety of haematologic malignancies. Next to inducing graft-vs-tumour effects, alloreactivity mediated by donor T-cells can be directed against normal host tissue (particularly the skin, liver, and gastrointestinal [GI] tract), manifesting as graft-vs-host disease (GVHD). GVHD, and especially GI-GVHD, is 1 of the major reasons for mortality and morbidity after allogeneic HCT. Clinically and endoscopically GI-GVHD resembles Crohn’s disease, and genetic association studies have implicated several genes associated with GVHD, including NOD2, a well-known inflammatory bowel disease (IBD) gene. In this study, we characterised a Dutch cohort of GVHD patients and hypothesised that genetic risk variants also play a role in GI-GVHD.


We clinically characterised a cohort form 2 university medical centres and collected DNA from both recipients and donors. These were genotyped using the Immunochip, a custom-made array including approximately 200 000 genetic variants, with dense coverage of immune-related genes. Cox regression analysis was used to correlate recipients and donor genotypes to GI-GVHD, including the time to development of GI-GVHD.


The cohort consisted of 151 patients (recipients) undergoing HCT. 72 (47%) patients developed GVHD, of which 24 (33%) developed substantial GI-GVHD (grade II, III, or IV). In total, 33/72 (45%) GVHD patients died, of which 9 (27%) causes of death could directly be related to GVHD. The incidence and mortality resembles cohorts described in the literature. We did not replicate the previously reported genetic associations at NOD2 for GVHD in GI-GVHD or in overall GVHD. We identified suggestive signals (p-value < 1E-4) for 16 loci. Loci harbouring JAK2, IL2RA, and the HLA-DRB1 contained multiple genetic variants, with signals for genetic association (JAK2 p-value 5.8E-5, IL2RA p-value 7.3E-6, and HLA-DRB1 p-value 1.85E-5).


In our Dutch cohort, GVHD is a frequently occurring complication of HCT, diminishing the prognosis of these patients. We did not replicate the previously reported association with NOD2, although the sample size equals that of those reported in literature. Because of insufficient power, we were unable to detect genetic association signals at genome-wide significance level, but we found suggestive evidence for associations for multiple genetic variants at loci harbouring JAK2, IL2RA, and the HLA locus. This implies that genetic variation in the immune system is likely to partly underlie the pathogenesis of (GI-) GVHD. Especially, the JAK2 association is interesting for follow-up because it was shown that JAK2 inhibition reduces GVHD in a mouse model and might be a promising therapeutic target.