title: BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.
abstract: The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants-other than HLA class I and II-associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R(2)=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10(-8); and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT.
authors.affiliation: Crs4, Biomedicine, Pula (CA), Italy.
authors.forename: Ignazio Stefano
authors.initials: IS
authors.lastname: Piras
authors.affiliation: Crs4, Biomedicine, Pula (CA), Italy.|IRGB, CNR, Monserrato (CA), Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Laboratory of Immunogenetics and Transplant Biology, IME Foundation, Polyclinic of Tor Vergata University, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Andreani
authors.affiliation: Laboratory of Immunogenetics and Transplant Biology, IME Foundation, Polyclinic of Tor Vergata University, Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Testi
authors.affiliation: International Center for Transplantation in Thalassemia and Sickle Cell Anemia, IME Foundation, Polyclinic of Tor Vergata University, Rome, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Lucarelli
authors.affiliation: Crs4, Biomedicine, Pula (CA), Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Floris
authors.affiliation: Pediatric Immuno-Hematology Unit and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Ospedale San Raffaele IRCCS, Milan.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Pediatric Immuno-Hematology Unit and Bone Marrow Transplantation Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Ospedale San Raffaele IRCCS, Milan.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: Centro Trapianti di Midollo Osseo, P.O. "R. Binaghi", Cagliari, Italy.|Department of Hematology, University of Cagliari, Cagliari, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: La Nasa
authors.affiliation: Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Katharina
authors.initials: K
authors.lastname: Fleischhauer
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSRTIGET), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.|Universita' Vita-Salute, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Roncarolo
authors.affiliation: Crs4, Biomedicine, Pula (CA), Italy.|bioflag Srl, Pula (CA), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bulfone
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSRTIGET), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gregori
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSRTIGET), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
mesh_terms: D000293:Adolescent; D000328:Adult; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D006084:Graft Rejection / Q000235:genetics*; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012306:Risk; D012307:Risk Factors; D017086:beta-Thalassemia / Q000235:genetics / Q000628:therapy
chemical_list: C092009:BAG6 protein, human; D006680:HLA Antigens; D018832:Molecular Chaperones; D011506:Proteins; C092008:PRRC2A protein, human
references.citation: J Biol Chem. 2008 Feb 8;283(6):3264-3271
references.pmid: 18056262
references.citation: Blood. 2012 Oct 4;120(14):2781-2
references.pmid: 23043027
references.citation: Expert Rev Mol Med. 2007 Nov 02;9(29):1-19
references.pmid: 17976248
references.citation: Genome Res. 2012 Sep;22(9):1790-7
references.pmid: 22955989
references.citation: Mol Biol Evol. 1995 Sep;12(5):921-7
references.pmid: 7476138
references.citation: FASEB J. 2012 Jan;26(1):104-16
references.pmid: 21940994
references.citation: PLoS One. 2012;7(4):e35972
references.pmid: 22558287
references.citation: Proc Natl Acad Sci U S A. 1990 Mar;87(6):2374-8
references.pmid: 2156268
references.citation: Hematology Am Soc Hematol Educ Program. 2010;2010:456-62
references.pmid: 21239835
references.citation: Int J Immunogenet. 2008 Aug;35(4-5):375-80
references.pmid: 18976441
references.citation: Nat Genet. 2008 Oct;40(10):1166-74
references.pmid: 18776908
references.citation: Blood. 2012 Jul 12;120(2):473-6
references.pmid: 22645178
references.citation: Genes Dev. 2007 Apr 1;21(7):848-61
references.pmid: 17403783
references.citation: Blood Rev. 2013 Jan;27(1):1-12
references.pmid: 23182478
references.citation: Genome Res. 2009 Mar;19(3):381-94
references.pmid: 19116412
references.citation: Nature. 2010 Sep 2;467(7311):52-8
references.pmid: 20811451
references.citation: Hum Genet. 1999 Sep;105(3):197-9
references.pmid: 10987645
references.citation: EMBO J. 1998 Nov 2;17(21):6135-43
references.pmid: 9799223
references.citation: Br J Haematol. 2002 Dec;119(4):1133-6
references.pmid: 12472598
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3568-71
references.pmid: 12824367
references.citation: Nucleic Acids Res. 2001 Nov 15;29(22):4724-35
references.pmid: 11713323
references.citation: Cancer Genomics Proteomics. 2006 Mar-Apr;3(2):113-118
references.pmid: 31394689
references.citation: Curr Stem Cell Res Ther. 2011 Jun;6(2):162-9
references.pmid: 21190532
references.citation: PLoS One. 2010 May 18;5(5):e10693
references.pmid: 20502693
references.citation: Haematologica. 2012 Jul;97(7):1014-9
references.pmid: 22271889
references.citation: Immunogenetics. 1992;35(6):355-64
references.pmid: 1349584
references.citation: Haematologica. 2011 Jan;96(1):128-33
references.pmid: 20935000
references.citation: Blood. 2012 Oct 4;120(14):2918-24
references.pmid: 22829628
references.citation: Cancer Sci. 2009 Jan;100(1):47-53
references.pmid: 19018758
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Curr Opin Pediatr. 2009 Feb;21(1):30-8
references.pmid: 19242239
references.citation: Mol Cell Biol. 2008 Nov;28(21):6720-9
references.pmid: 18765639
references.citation: Biol Blood Marrow Transplant. 2007 Nov;13(11):1358-68
references.pmid: 17950922
references.citation: Nat Med. 2012 Sep;18(9):1394-400
references.pmid: 22863785