title: Genotypes and haplotypes in the 3' untranslated region of the HLA-G gene and their association with clinical outcome of hematopoietic stem cell transplantation for beta-thalassemia.
abstract: Polymorphisms in the 3' untranslated region (3'UTR) of HLA-G, an important player in immunological tolerance, could be involved in post-transcriptional expression control, and their association with different clinical immune-related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single-nucleotide polymorphisms (SNPs) in the HLA-G 3'UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3'UTR haplotypes of HLA-G, or the 14 bp ins/del, with clinical outcome of HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta-thalassemia patients. Sequence based typing of 3'UTR HLA-G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3'UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation-maximization studies, with four predominant haplotypes (UTRs1-4). After HSCT, we found a moderate though not significant association between the presence of UTR-2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14-1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16-1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3'UTR HLA-G haplotypes for risk prediction after allogeneic HSCT for beta-thalassemia.
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy. sizzano.federico@hsr.it
authors.forename: F
authors.initials: F
authors.lastname: Sizzano
authors.forename: M
authors.initials: M
authors.lastname: Testi
authors.forename: L
authors.initials: L
authors.lastname: Zito
authors.forename: R
authors.initials: R
authors.lastname: Crocchiolo
authors.forename: M
authors.initials: M
authors.lastname: Troiano
authors.forename: B
authors.initials: B
authors.lastname: Mazzi
authors.forename: G
authors.initials: G
authors.lastname: Turchiano
authors.forename: M
authors.initials: M
authors.lastname: Torchio
authors.forename: C
authors.initials: C
authors.lastname: Pultrone
authors.forename: S
authors.initials: S
authors.lastname: Gregori
authors.forename: R
authors.initials: R
authors.lastname: Chiesa
authors.forename: J
authors.initials: J
authors.lastname: Gaziev
authors.forename: P
authors.initials: P
authors.lastname: Sodani
authors.forename: S
authors.initials: S
authors.lastname: Marktel
authors.forename: A
authors.initials: A
authors.lastname: Amoroso
authors.forename: M G
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: G
authors.initials: G
authors.lastname: Lucarelli
authors.forename: F
authors.initials: F
authors.lastname: Ciceri
authors.forename: M
authors.initials: M
authors.lastname: Andreani
authors.forename: K
authors.initials: K
authors.lastname: Fleischhauer
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics* / Q000276:immunology; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D059951:HLA-G Antigens / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007108:Immune Tolerance; D007558:Italy; D015810:Linkage Disequilibrium; D008297:Male; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D035781:Siblings; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D017086:beta-Thalassemia / Q000235:genetics* / Q000276:immunology / Q000628:therapy
chemical_list: D020413:3' Untranslated Regions; D059951:HLA-G Antigens