title: ATM gene single nucleotide polymorphisms predict regimen-related gastrointestinal toxicity in patients allografted after reduced conditioning.
abstract: Polymorphisms of genes involved in innate and adaptive immunity have become an object of major interest in regard to hematopoietic stem cell transplantation (HSCT) complications. Regimen-related gastrointestinal toxicity (RR-GIT) is the dominant complication during the pre-engraftment period and has been linked to increased risk of graft-versus-host disease (GVHD) development. According to our hypothesis, functional variants of genes participating in DNA damage response (DDR) may have an impact on the extent of tissue damage caused by the conditioning regimen. In our single-center study, we analyzed 62 patients who underwent HSCT from HLA-identical donors after reduced conditioning. The patients were genotyped for 5 single nucleotide polymorphisms (SNPs, rs4585 T/G, rs189037 A/G, rs227092 T/G, rs228590 C/T, and rs664677 T/C) of the ATM gene-the essential member of the DDR pathways, using allele-specific matrix-assisted laser desorption/ionization, time-of-flight (MALDI-TOF) mass spectrometry assay. Because of almost absolute linkage disequilibrium observed among all 5 SNPs, association of 2 major ATM haplotypes (ATM1/ATM2) with RR-GIT and acute GVHD (aGVHD) was analyzed. Importantly, the univariate and multivariate analysis showed that patients homozygous for ATM2 haplotype (rs4585*T, rs189037*A, rs227092*T, rs228590*C, and rs664677*T) are more likely to suffer from high-grade RR-GIT than ATM1 homozygous patients. The association with aGVHD was not significant. To our knowledge, this is the first report showing the ATM gene variability in relation to RR-GIT in the allogeneic HSCT setting.
authors.affiliation: Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address: adam.kuba@fnol.cz.
authors.forename: Adam
authors.initials: A
authors.lastname: Kuba
authors.affiliation: Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Ludek
authors.initials: L
authors.lastname: Raida
authors.affiliation: Department of Immunology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Mrazek
authors.affiliation: Department of Immunology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Schneiderova
authors.affiliation: Department of Immunology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Kriegova
authors.affiliation: Department of Mathematical Analysis and Applications of Mathematics, Faculty of Science, Palacky University, Olomouc, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Furst
authors.affiliation: Department of Mathematical Analysis and Applications of Mathematics, Faculty of Science, Palacky University, Olomouc, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Furstova
authors.affiliation: Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Edgar
authors.initials: E
authors.lastname: Faber
authors.affiliation: Department of Immunology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Ambruzova
authors.affiliation: Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Papajik
mesh_terms: D000208:Acute Disease; D000328:Adult; D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000276:immunology; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D005787:Gene Frequency; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000401:mortality; D006239:Haplotypes; D019337:Hematologic Neoplasms / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
chemical_list: D019653:Myeloablative Agonists; D020033:Protein Isoforms; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM gene; Acute graft-versus-host disease; Allogeneic hematopoietic stem cell transplantation; Gastrointestinal toxicity; Single-nucleotide polymorphism