P678. Relation between a single nucleotide polymorphism in MORC4, NOD2 variants and outcome after allogeneic stem cell transplantation for haematological malignancies
E. Norén1, D. Verma2, J. Söderman3, K. Lotfi4, S. Almer1, 1Linköping University, Department of Clinical and Experimental Medicine, Linköping, Sweden, 2University of California, Department of Paediatrics, San Diego, United States, 3Ryhov County Hospital, Division of Medical Diagnostics, Jönköping, Sweden, 4Linköping University Hospital, Department of Hematology, Linköping, Sweden
There is comparable pathophysiology in inflammatory bowel disease (IBD) and graft-versus-host-disease (GVHD) after allogeneic stem cell transplantation (SCT) for haematological malignancies. Some studies have found an association between the three most common single nucleotide polymorphisms (SNP) in NOD2 (R702W, G908R and 3020insC) and an increased incidence of acute GVHD. We have recently in a case-control approach found a genetic association between a marker in MORC4 and Crohn's disease. MORC4 is linked to the transforming growth factor-beta signalling pathway. Based on the pathophysiology of IBD and GVHD, we speculated that the genetic pattern seen in IBD might have impact on the emergence of acute GVHD and mortality risk.
Adult patients (n = 111, median age 49 (IQR 39–57), 64 men) with haematological malignancies that underwent SCT from May 1996 to April 2005 were included. A MORC4 SNP and the three most common SNPs in NOD2 were investigated for genetic associations to the occurrence of acute GVHD and the mortality risk after SCT, using a case-control approach.
Forty patients (27 men) died within twelve months after SCT. Since the marker for MORC4 is located on the X-chromosome, we stratified the patients into two groups, men and women. For men (allelic OR = 4.21, 95% CI 1.31–13.48, p = 0.012), but not for women (allelic OR = 1.53, 95% CI 0.68–3.45, p = 0.304), the association between MORC4 and mortality was significant. However, a heterogeneity test could not identify a significant distinction between men and woman and, additionally, the Mantel–Haenszel estimate of the common OR for association between the MORC4 marker and mortality significant (allelic OR = 2.17, 95% CI 1.10–4.29, p = 0.019). Five, 2 and 5 were heterozygous for at least one of the three SNPs of NOD2 (R702W, G908R and 3020insC), respectively, corresponding to 11% of patients (12/111). One patient was compound heterozygous for G908R and 3020insC. On the basis of carrying none or at least one NOD2 mutant allele, borderline significant association was identified between NOD2 (allelic OR = 4.21, 95% CI 0.90–19.69, p = 0.071) and mortality. Additionally, no significant association was identified between MORC4 or NOD2 and acute GVHD.
In conclusion, these findings reinforce a concept where GVHD and IBD share a subset of genetic susceptibility factors, and may lead to a better understanding of GVHD pathogenesis after SCT for haematological malignancy.