title: Genetic variation in donor CTLA-4 regulatory region is a strong predictor of outcome after allogeneic hematopoietic cell transplantation for hematologic malignancies.
abstract: Relapse remains a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Graft-versus-tumor effect is primarily mediated by donor T cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a critical inhibitor of T cell proliferation. Single nucleotide polymorphisms (SNPs) in CTLA-4 may affect immune responses. We hypothesized that CTLA-4 SNPs will be associated with disease control after allo-HCT. One hundred sixty-four adult patients with the availability of pretransplantation recipient and donor DNA samples were included in this analysis. Ten tagSNPs of the CTLA-4 gene were identified. Donor CTLA-4 SNP rs4553808 was associated with decreased relapse-free survival (RFS) (P = .019) and overall survival (OS) (P = .033). In multivariable analysis of an additive genetic model, genotype of CTLA-4 SNP rs4553808 was an independent risk factor for inferior RFS (hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.10-2.71, P = .017) and OS (HR = 1.84, 95% CI 1.13-3.0, P = .015). CTLA-4 SNPs can be used to identify high-risk patient subsets that may benefit from preemptive immunomodulation to decrease relapse rates and improve survival.
authors.affiliation: Hematology and Stem Cell Transplantation Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. madan.jagasia@vanderbilt.edu
authors.forename: Madan
authors.initials: M
authors.lastname: Jagasia
authors.forename: William B
authors.initials: WB
authors.lastname: Clark
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Brown-Gentry
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Kang-Hsien
authors.initials: KH
authors.lastname: Fan
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.forename: Adetola
authors.initials: A
authors.lastname: Kassim
authors.forename: John P
authors.initials: JP
authors.lastname: Greer
authors.forename: Brian G
authors.initials: BG
authors.lastname: Engelhardt
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D005260:Female; D020350:Graft vs Tumor Effect / Q000276:immunology; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000276:immunology; D012307:Risk Factors; D055502:Secondary Prevention; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D060908:CTLA-4 Antigen