SNP12 and SNP13 Variants of NOD2/CARD15 Gene of Donor and Recipient as Independent Risk Factors for Severe Intestinal and Pulmonary GVHD after Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract

Background: Presence of any of single nucleotide polymorphism (SNPs) of the NOD2/CARD15 gene have been recently proven to correlate with higher rate of GvHD after allogeneic hematopoietic stem cell transplantation - alloHSCT (Holler E et al; Blood 2006, 107,4189). Mutated variants lead to impaired antibacterial response. As NOD2/CARD15 is expressed not only in monocytets/macrophages but also in both intestinal and bronchial epithelial cells these organs seem to be a major target for developing advanced GvHD.Patients and methods: The impact of each single donor (D) and recipient (R) SNPs (8,12,13) of NOD2/CARD15 gene on the incidence of acute GvHD (grade II-IV, grade III-IV, intestinal), chronic GvHD (overall, extensive, pulmonary), survival, and non-relapse mortality was evaluated in a setting of 72 patients treated with alloHSCT in single BMT center in Katowice between Jan 2000 and Jun 2005. Median patient age was 33 (11–52) years. In 70/72 cases hematological malignancies were indication for alloHSCT. Conditioning regimen was myeloablative in all cases, bone marrow was used as the only source of stem cells in 74% of patients. GVHD prophylaxis consisted of CsA, Mtx and, in case of URD-HSCT - antithymocyte globulin.Results: In univariate and multivariate analysis, including other potential risk factors, the presence of SNP12 in the recipient was associated with increased incidence of intestinal acute GVHD (75% vs. 29%; RR 4,37, p=0,03), overall chronic GVHD (100% vs. 50%, RR 4,72; p=0,003), extensive chronic GVHD (80% vs. 24%; RR 5,12; p=0,02), and pulmonary chronic GVHD (47% vs. 9%; RR 5,97; p=0,02). SNP13 in the recipient resulted in increased incidence of grade III–IV acute GVHD (45% vs. 12%; RR 4,66; p=0,01), intestinal acute GVHD (64% vs. 24%; RR 4,21, p=0,005), and extensive chronic GVHD (55% vs. 25%; RR 3,59; p=0,03). SNP13D in the donor contributed to increased risk of pulmonary chronic GVHD (36% vs. 8%; RR 6,58; p=0,01). In this single centre analysis we were not able to demonstrate the impact of NOD2/CARD15 SNPs on survival.Conclusion: The presence of particular mutations of NOD2/CARD15 in the recipient and/or the donor is associated with increased risk of severe acute and chronic GVHD. In particular, intestines and lungs appear to be target organs of these complications. Our findings may contribute to optimization of immunosuppressive and gastrointestinal decontamination regimens based on individual risk assessment for GVHD.