Donor and Recipient Genotypes for Interleukin 1 Gene Single Nucleotide Polymorphisms (SNPs) Allow Anticipation of Acute Graft Versus Host Disease after HLA-Identical Allogeneic Stem Cell Transplantation (allo-SCT)
Authors: Buces Elena , Martínez-Laperche Carolina , González-Rivera Milagros , Bosch-Vizcaya Anna , Martin-Antonio Beatriz , Guillem Vicent , Nieto Jose B , González Marcos , De La Camara Rafael , Brunet Salut , Jimenez-Velasco Antonio , Espigado Ildefonso , Vallejo Carlos , Sampol Antonia , Bellon Jose Maria , Serrano David , Kwon Mi , Gayoso Jorge , Pascual Balsalobre , Urbano-Izpizua Alvaro , Solano Carlos , Gallardo David , Díez Martín José Luis , Buno Ismael 
Published: October 2019

Introduction.

Graft versus host disease (GvHD) is the main cause of morbimortality after allogeneic stem cell transplantation (allo-SCT). Several single-nucleotide polymorphisms (SNPs) in cytokine genes have shown to influence gene expression and are therefore associated with donor-recipient alloreactivity and, ultimately, with SCT outcome. Interleukin 1 (IL1) is a proinflammatory cytokine that induces the production of cytokines and chemokines and plays an important role in the inflammatory processes. IL1 is involved in various cellular functions, including cell proliferation, differentiation, and apoptosis. The IL1 family consists of two biologically actives forms (IL1A and IL1B). Several polymorphisms of these genes have been implicated in the pathogenesis of autoimmune diseases, however, their importance in SCT is not well-known.

Objective

To investigate the relationship between 4 SNPs in IL1A and IL1B genes and the susceptibility to the development of GvHD and other complications after HLA-identical allo-SCT.

Patients and methods

Genomic DNA obtained from peripheral blood samples belonging to 509 patients and their HLA-identical sibling donors (Table 1) included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation (GETH). One SNP, rs1800587 (-889 C>T), in the promoter region of the IL1A gene and three SNPs in the IL1B gene (two in the promoter region rs16944 (-511C>T), rs1143627 (-31 T>C) and one in exon 5 rs1143634 (+3954 C>T) were genotyped by multiplex primer extension followed by mass spectrometry (MALDI-TOF; Sequenom MassArray).

Univariate and multivariate regression analysis were performed using Cox regression in the presence of competing risks except for chronic GvHD for which we used logistic regression model. All variables with p≤0.10 according to univariate analysis were included in the multivariate analysis. For multivariate analyses, p values were two sided and the outcomes were considered to be significant for p<0.05. All analyses were performed by R Statistical Software ver. 2.15.0.

Results

Genotypic frequencies observed for the 4 SNPs analyzed were in accordance with the Hardy-Weinberg equilibrium and were similar to those previously reported. Results of the multivariate analysisof the association between IL1A and IL1B genotypes and complications after allo-SCT are shown in Table 2.

No association between the SNPs analyzed and complications other than acute GVHD were found. Patients with the alloreactive TT genotype for the SNP rs1143627 show increased risk of grade II-IV and III-IV acute GvHD (HR=6.87 and HR=19.19 respectively). In addition the presence of the rs16944 alloreactive A allele in the recipient was also associated with a significantly higher incidence of grade II-IV and mainly III-IV acute GvHD (HR=11.85 for grade II-IV and HR=53.48 for grade III-IV) Finally a higher risk of grades III-IV acute GvHD was observed in patients harboring alloreactive TT genotype for SNP rs1800587 (HR=3.12).

Conclusions

These results further support the idea of a genetic predisposition to certain complications after allo-SCT especially GvHD. IL1A and IL1B SNP genotyping might be useful to anticipate complications after sibling HLA-identical allo-SCT and, therefore to tailor the use of immunomodulatory approaches and, ultimately, to improve the clinical management of transplanted patients.

Figure 1 Figure 1.

Figure 2 Figure 2.

Disclosures

No relevant conflicts of interest to declare.