Genetic Polymorphisms in the Inflammasomes Are Associated with Relapse and Survival in HLA-Identical Sibling Donor Allogeneic Stem Cell Transplantation.

Abstract

The inflammasomes are intracellular multiprotein complexes responsible of the secretion of IL-1β in response to the recognition of microbial patterns. Polymorphisms of genes codifying for inflammasomes proteins might influence the clinical outcome of patients receiving allogeneic stem cell transplantation (allo-SCT). Fourteen single nucleotide polymorphisms (SNPs) in NALP1, NALP2, NALP3, CARDINAL and CASPASE5 were genotyped by allelic discrimination in 133 adult donor-patient pairs undergoing sibling donor allo-SCT in a single institution. Patient median age was 41 years (range 17–64) and 61% were males. All patients were diagnosed with hematological malignancies; 71% of them were in advanced phase at transplantation. Median follow-up of the surviving patients was 39 months (range 1–118). Actuarial probabilities of relapse, non-relapse mortality (NRM) and overall survival (OS) were 40% (95% CI 39–41), 35% (95% CI 34–36) and 48% (95% CI 47–49), respectively. Genotype frequencies were similar to those published at NCBI database. NALP2 rs1043684 and rs1043673 (p<0.0001) as well as NALP3 rs10925027 and rs10754558 (p<0.0001) were inherited in linkage disequilibrium. NALP2 rs1043684 (GG 25% vs. GA/AA 12%, p=0.09) was the only factor weakly associated with severe acute GVHD. At multivariate analysis, donor NALP3 rs10925027 TT genotype was associated with relapse (RR 4.22, p=0.000001). Patient NALP1 rs5862 AA genotype and donor NALP2 rs1043684 GG were associated with NRM (RR 5.11, p=0.0002 and RR 2.97, p=0.005, respectively), and OS (RR 2.15, p=0.011 and RR 2.81, p=0.003, respectively). Inflammasome genetic SNPs of both donor and patient influence the outcome of allo-SCT. If these findings are validated in other series, genotype of NALP genes would become an important factor in donor selection.