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

• Published in: Tissue antigens Vol. 79; no. 5; pp. 326 - 332
• Main Authors: Sizzano, F., Testi, M., Zito, L., Crocchiolo, R., Troiano, M., Mazzi, B., Turchiano, G., Torchio, M., Pultrone, C., Gregori, S., Chiesa, R., Gaziev, J., Sodani, P., Marktel, S., Amoroso, A., Roncarolo, M. G., Lucarelli, G., Ciceri, F., Andreani, M., Fleischhauer, K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2012
• Subjects: 3' Untranslated Regions - genetics; 3' Untranslated Regions - immunology; 3′ untranslated region; Adolescent; Adult; beta-Thalassemia - genetics; beta-Thalassemia - immunology; beta-Thalassemia - therapy; Case-Control Studies; Child; Child, Preschool; Female; Genotype; genotypes; Graft vs Host Disease - diagnosis; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; haplotypes; Haplotypes - genetics; Haplotypes - immunology; Hematopoietic Stem Cell Transplantation; HLA-G Antigens - genetics; human leukocyte antigen-G; Humans; Immune Tolerance; Italy; Linkage Disequilibrium; Male; Mutagenesis, Insertional; Polymorphism, Genetic; polymorphisms; population studies; Sequence Deletion; Siblings; thalassemia; Transplantation, Homologous; Treatment Outcome; Italy
• ISSN: 0001-2815; 1399-0039
• DOI: 10.1111/j.1399-0039.2012.01862.x

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.