Single Nucleotide Polymorphism of CC Chemokine Ligand 5 Promoter Gene in Recipient May Affect on the Development of Chronic Graft-Versus-Host Disease and Its Severity after Allogeneic Transplantation.

Background: The leukocyte trafficking, which is critically regulated by chemokine ligands and their receptors, has been known to be involved in the pathogenesis of graft-versus-host disease (GVHD). CC ligand 5 (CCL5; previously called as RANTES) is expressed on antigen-presenting cells, endothelium, and epithelium, while CC receptor 5 (CCR5) is expressed on type 1 T-cells. The current study analyzed the association of CCR5/CCL5 gene single nucleotide polymorphisms (SNPs) on both side of recipients and donors with acute or chronic GVHD (cGVHD) after allogeneic transplantation.

Methods and patients: We evaluated the SNPs of CCL5 promoter gene at loci −28/−403 and CCR5 gene at 59029 in 72 recipients and 107 donors using PCR/RFLP methods with genomic DNAs. The associations of acute/cGVHD and its severity with CCL5/CCR5 SNPs of recipients/donors were examined using chi-square test, while the incidences of acute/cGVHD were also compared by Log-rank test.

Results: With a median follow up of 924 days for survivors (range 48~2,360 days), the CG genotype of CCL5 gene −28 loci of recipients was significantly associated with a higher incidence of overall cGVHD (p=0.004), extensive cGVHD (p=0.038 by Seattle criteria) and severe grade of cGVHD at presentation compared to CC genotype (p=0.017 by prognostic grading by Apkek et al). The patients with AG haplotype of CCL5 SNP of recipients also showed a higher incidence of overall cGVHD (p=0.003), extensive cGVHD (p=0.023), and more severe grade of cGVHD (p=0.020). However, the CG genotype at CCL5, −28 and AG haplotype did not correlate with the clinical course of cGVHD in terms of GVHD-specific survival or the duration of systemic immunosuppressive therapy. In addition, an association of CCL5/CCR5 SNPs with acute GVHD was not noted. The SNP of CCL5/CCR5 of donors did not influence the occurrence of cGVHD.

Conclusion: The CCL5 promoter gene polymorphism of recipients may be associated with the development of cGVHD and its severity. The current study suggested an involvement of CCL5 in leukocyte trafficking for the development of cGVHD.