Chemokine Receptor Gene Polymorphisms and Severity of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Sibling Donors.

Background: Single nucleotide polymorphisms (SNPs) and other genetic variations in various genes involved in the immune response have been variably associated with acute graft-versus-host-disease (GVHD). The interaction of chemokines with their receptors is crucial for organ-specific recruitment of immune cells. Trafficking of recipient antigen presenting cells as well as donor lymphocytes between lymph nodes and target tissues are especially important events in acute GVHD pathogenesis. In this pilot, retrospective study, we sought to examine the role of recipient and donor chemokine receptor gene polymorphisms in determining the incidence of severe acute GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from matched sibling donors.

Methods: Patient and donor samples were genotyped for the following chemokine receptor polymorphisms: CCR5 -59029 A/G, CCR2 190 A/G (V64I), CX3CR1 745 A/G (V249I) and CX3CR1 839 C/T (T280M) and CCR5Δ32. Due to the extreme rarity of homozygosity for the Δ32 deletion in CCR5, the CCR5Δ32 homozygotes and heterozygotes were grouped together for analysis. The relationship between polymorphism genotypes and acute GVHD outcomes (Grade 0 vs Grades III/IV) were evaluated.

Results: A total of 103 donor-recipient pairs were analyzed which included 58 recipients who experienced severe acute GVHD (Grades III/IV) and 45 recipients who did not develop acute GVHD (Grade 0). Compared to the wild type CCR5 allele, the presence of the CCR5Δ32 allele in the donor conferred an increased risk for severe acute GVHD (P=0.04). The odds ratio is estimated to be 6.16 (95% CI [0.73, 52.05]). Presence of CCR5Δ32 in the recipient was not associated with increased acute GVHD risk (P=0.14). For the CCR5 -59029 A/G polymorphism, there was the suggestion of a decreased trend for developing severe acute GVHD if the donor had the A/A genotype (P=0.09). A trend for an association with the incidence of severe acute GVHD was observed for the CCR2 V64I polymorphism in the recipient. (P= 0.08). Donor genotype for this polymorphism was not associated with severe GVHD (P=0.17). A trend towards increased incidence of severe GVHD was observed for the 745 A/G (V249I) polymorphism (P=0.1). No significant effect was observed for the CX3CR1 839 C/T (T280M) polymorphism in this study.

Conclusions: CCR5Δ32 polymorphism in the donor was associated with severe acute GVHD in this study. This and other functional chemokine receptor polymorphisms are potential candidates for evaluation in large prospective studies in future to precisely determine their association with acute GVHD.