A Single Nucleotide Polymorphism in the NLRP3 Gene Is Associated with Acute Graft-Versus-Host Disease After HLA-Matched Unrelated Bone Marrow Transplantation,

NOD-like receptor family, pyrin domain containing 3 (NLRP3) is an innate immune receptor that exerts functions in the regulation of inflammation and apoptosis. Recent studies have shown that the single nucleotide polymorphism (SNP) rs10754558 (C>G) at the 3' untranslated region of NLRP3 gene is functional and is associated with various immunological diseases. Allele G is linked with a higher activity of NLRP3 than allele A, and plays important roles in increased susceptibility to allergic reactions and in protection of HIV infection. This study retrospectively examined the impact of the NLRP3 genotype of a total 659 recipients with hematologic malignancies and their unrelated donors on the clinical outcomes in unrelated HLA 12/12 matched bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The genotype frequencies of G/G, G/C and C/C were 19%, 50% and 31% in recipients and 18%, 49% and 32% in donors (P =0.79). The donor G/G or G/C genotype was associated with a significantly higher incidence of grades III to IV acute graft-versus-host disease (GVHD; 15% vs. 7%, P =0.004; Fig 1B) and a trend toward a higher incidence of grades II to IV acute GVHD (34% vs. 27%, P =0.06; Fig 1A), while no significant differences between the G/G genotype and G/C genotype were seen. The donor G/G or G/C genotype remained statistically significant in the multivariate analysis for the development of grades III to IV acute GVHD (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.22 to 3.90; P =0.009) as well as a trend toward an association with grades II-IV acute GVHD (HR, 1.31; 95% CI, 0.96 to 1.80; P =0.09). The recipient NLRP3 genotype did not significantly influence the transplant outcomes. These results suggest an association of the donor NLRP3 genotype with the development of acute GVHD after unrelated BMT. Genotyping for the NLRP3 rs10754558 could be useful in donor selection and risk-adapted management of transplanted patients, and may furthermore offer some novel therapeutic insights into the mechanisms of acute GVHD.