Donor Single Nucleotide Polymorphism in the CCR9 Gene Affects the Incidence of Acute Skin Graft-Versus-Host Disease
Authors: Inamoto Yoshihiro , Murata Makoto , Kuwatsuka Yachiyo , Tsujimura Akane , Sugimoto Kyoko , Oba Taku , Onizuka Makoto , Terakura Seitaro , Katsumi Akira , Miyamura Koichi , Kodera Yoshihisa , Naoe Tomoki 
Published: April 2020

Abstract
Chemokines are a group of small molecules that regulate trafficking of leukocytes through interactions with a subset of seven-transmembrane, G protein-coupled chemokine receptors. Their interactions may play an important role in initiating acute graft-versushost disease (GVHD) after allogeneic hematopoietic stem cell transplanation. CCR9 is a very unique receptor because, outside of the thymus, it is almost exclusively expressed by epithelial cells and Pyer’s patches in the small intestine. We focused on rs12721497 (G926A), one of the single nucleotide polymorphisms (SNPs) in the CCR9 gene, and analyzed the impact of its genotype on the onset of organ-specific acute GVHD and transplant outcome. Included in the study were consecutive patients who had received allogeneic bone marrow or peripheral blood stem cell transplantation from an HLA-identical sibling donor at the Nagoya University Hospital and the Japanese Red Cross Nagoya First Hospital between 1987 and 2006. Of these, a total of 167 patients who received T cell replete transplantation with short-term methotrexate and cyclosporine as a GVHD prophylaxis were analyzed. Informed consent was obtained from all patients and donors, and the study was approved by the ethics committees at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital. The CCR9 G926A genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method using genomic DNA obtained from donor cells. The impact of CCR9 genotype on the incidence of acute GVHD in each organ, overall survival rates, relapse rates and nonrelapse mortality rates were analyzed using the Cox proportional hazard regression model. Age, intensity of conditioning, total body irradiation, disease risk, remission state and graft source were used as covariates for adjustment. Median age was 38 years old (range 15–62). Diseases were malignancies (n=148) and non-malignancies (n=19). The incidences of acute GVHD were 22% (grade I), 12% (grade II) and 6.6% (grade III-IV). The frequencies of the AA, AG and GG genotype were 94%, 6% and 0%, respectively. CCR9 926AG genotype was significantly associated with the incidence of stage³2 skin GVHD (hazard ratio 3.2; 95% CI, 1.1–9.1), but not associated with the incidence of liver GVHD, intestinal GVHD, grade II-IV GVHD, overall survival rates, relapse rates and nonrelapse mortality rates. In conclusion, the frequencies of each genotype were compatible with the reports in HapMap database. It was notable that donor CCR9 SNPs affected the incidence of skin GVHD, but did not affect that of intestinal GVHD. Beilhack et al. (Blood. 2008;111:2919–2928) recently reported redundancy of secondary lymphoid organs at different anatomical sites in GVHD initiation. They suggested that primed T cells could initiate GVHD at different sites from their original priming sites. Since Pyer’s patches are important as sites of antigen presenting, T cell homing to Pyer’s patches may be different between each CCR9 926AG genotype, resulting in different incidences of skin GVHD. We are now investigating the functional differences between each genotype.