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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4623-4624. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Azarian, M. Articles by Socié, G. Search for Related Content PubMed PubMed Citation Articles by Azarian, M. Articles by Socié, G. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents CORRESPONDENCE Donor CTLA-4 +49 A/G*GG genotype is associated with chronic GVHD after HLA-identical haematopoietic stem-cell transplantations To the editor: The CTLA-4 gene encodes a molecule providing a negative signal for T-cell activation. CTLA-4+49A/G and CT60 polymorphisms have been associated with auto-immune diseases (AID).1,2 A recent study suggested that donor genotype AA of CT60 was associated with better survival, increased rate of acute graft-versus-host disease (GVHD) and lower relapse incidence.3 We evaluated the impact of +49A/G and CT60 polymorphisms in 225 patients who received, after a myeloablative conditioning regimen, a non–T-depleted hematopoietic stem-cell transplant (HSCT) from a human leukocyte antigen (HLA)–identical sibling donor for malignant diseases. The donors were genotyped for +49A/G and CT60 using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) techniques.1,4 The patient, donor, and transplant characteristics were not statistically different with respect to +49 A/G and CT60 polymorphisms. The end points were acute GVHD, chronic GVHD (cGVHD), relapse, survival, and bacterial, fungal, and cytomegalovirus (CMV) infections. We did not find any association of donor +49A/G or CT60 polymorphisms nor of +49A/G /CT60 genotypes with acute GVHD, relapse, survival, or infections. However, patients who received a graft from a donor with a GG genotype for +49A/G had a stronger risk of developing cGVHD compared with those having a donor with either AG or AA genotype (73% vs 55% or 48%, respectively, P = .04). The same tendency without statistical significance was observed for CT60*GG genotype (62% vs 54% or 40%, respectively, P = .06). In fact, CT60*GG and +49A/G*AA or AG had the same risk of cGVHD as CT60*AA and +49A/G*AA or AG genotypes (56% and 50%, respectively) and a statistically significant lower risk than the CT60*GG and +49A/G*GG genotype (73%, P = .04). CT60 polymorphism did not appear to be an independent risk factor of cGVHD. This is due to the linkage disequilibrium between +49A/G*G and CT60*G polymorphisms. In Cox multivariate analysis (backward stepwise, logistic regression), when studying +49A/G polymorphisms, age of the patients, ABO incompatibilities, stage of disease, source of stem cells, and sex matching, as potent pregraft risk factors for cGVHD, 3 factors appeared to be independent risk factors of cGVHD: +49A/G (P = .03, hazard ratio [HR] = 1.76, 95% confidence interval [CI] 1.01-2.95), age of the patient (P = .01, HR = 2.28, 95% CI 1.21-4.27), and ABO incompatibility (P = .03, HR = 1.55, 95% CI 1.04-2.31). While this study did not confirm the association of donor CT60 polymorphism with acute GVHD, relapse, and survival as suggested by Perez-Garcia,3 it showed a significant association of donor +49A/G*GG genotype with cGVHD. In vitro studies have shown that the +49A/G* GG genotype correlated with an increased T-cell proliferation after stimulation4 and decreased expression of CTLA-4.5 This effect was seen in CD4+and not in CD8+ T lymphocytes.6 In vitro studies as well as the association with autoimmune disease (AID) support the fact that the +49A/G*GG genotype is associated with an increased CD4+ T-cell response to stimulation. As CD4+T cells play an important role in the occurrence of cGVHD, their increased activation in association with +49A/G*GG genotype could explain the observed association of +49A/G*GG genotype with cGVHD. These results illustrate the increasing role of non–HLA genetics in developing an HSCT risk index for use in the clinic.7 Authorship Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Pascale Loiseau, Hôpital Saint-Louis, Laboratoire d'Immunologie et d'Histocompatibilité, 1 Avenue Claude Vellefaux, 75010 Paris, France; e-mail:pascale.loiseau{at}univ-paris-diderot.fr. Mariam Azarian, Marc Busson, Virginia Lepage, Dominique Charron, Antoine Toubert, Pascale Loiseau, Regis Peffault de Latour, Vanderson Rocha, and Gerard Socié References Ueda H, Howson JMM, Esposito L, et al. Association of the T-cell regulatory gene CTLA-4 with susceptibility to autoimmune disease. Nature 2003; 423:506–511.[CrossRef][Medline] [Order article via Infotrieve] Kristiansen OP, Larsen ZM, Pociot F. CTLA-4 in autoimmune diseases- a general susceptibility gene to autoimmunity. Genes Immun 2000; 1:170–184.[Medline] [Order article via Infotrieve] Pérez-García A, De la Camara R, Roman-Gomez J, et al. CTLA-4 polymorphisms and clinical outcome after allogeneic stem cell transplantation from HLA-identical sibling donors. Blood 2007; 110:461–467.[Abstract/Free Full Text] Kouki T, Sawai Y, Gardine CA, et al. CTLA-4 Gene Polymorphism at position 49 in Exon 1 Reduces the Inhibitory Function of CTLA-4 and Contributes to the Pathogenesis of Graves' Disease. J Immunol 2000; 165:6606–6611.[Abstract/Free Full Text] Anjos S, Nguyen A, Ounissi-Benhalkar H, et al. A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J Biol Chem 2002; 277:46478–46486.[Abstract/Free Full Text] Ligers A, Teleshova N, Masterman T, et al. CTLA-4 gene expression is influenced by promoter and exon 1 polymorphism. Genes Immun 2001; 2:145–152.[CrossRef][Medline] [Order article via Infotrieve] Dickinson AM and Charron D. Non-HLA immunogenetics in hematopoietic stem cell transplantation. Curr Opin Immunol 2005; 17:517–525.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Azarian, M. Articles by Socié, G. Search for Related Content PubMed PubMed Citation Articles by Azarian, M. Articles by Socié, G. Social Bookmarking                   What's this?

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