A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation.
Interleukin IL-17 is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. The single nucleotide polymorphism (SNP), rs2275913, in the promoter region of the IL-17 gene is associated with susceptibility to ulcerative colitis. When we examined the impact of rs2275913 in a cohort consisting of 438 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program, the donor IL-17 197A allele was found to be associated with a higher risk of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00 to 2.13; P = 0.05). Next, we investigated the functional relevance of the rs2275913 SNP. In vitro stimulated T cells from healthy individuals possessing the 197A allele produced significantly more IL-17 than those without the 197A allele. In a gene reporter assay, the 197A allele construct induced higher luciferase activity than the 197G allele, and the difference was higher in the presence of T cell receptor activation and was abrogated by cyclosporine treatment. Moreover, the 197A allele displayed a higher affinity for the nuclear factor activated T cells (NFAT), a critical transcription factor involved in IL-17 regulation. These findings substantiate the functional relevance of the rs2275913 polymorphism and indicate that the higher IL-17 secretion by individuals with the 197A allele likely accounts for their increased risk for acute GVHD and certain autoimmune diseases.
Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa, Japan.
J Luis
JL
Espinoza
Akiyoshi
A
Takami
Katsuya
K
Nakata
Makoto
M
Onizuka
Takakazu
T
Kawase
Hideki
H
Akiyama
Koichi
K
Miyamura
Yasuo
Y
Morishima
Takahiro
T
Fukuda
Yoshihisa
Y
Kodera
Shinji
S
Nakao
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D061349:Unrelated Donors; D055815:Young Adult
D020381:Interleukin-17; D050778:NFATC Transcription Factors