title: NOD2/CARD15 single nucleotide polymorphism 13 (3020insC) is associated with risk of sepsis and single nucleotide polymorphism 8 (2104C>T) with herpes viruses reactivation in patients after allogeneic hematopoietic stem cell transplantation.
abstract: Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade ≥ II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen.
authors.affiliation: L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Jaskula
authors.affiliation: L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland; Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland. Electronic address: lange@iitd.pan.wroc.pl.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Lange
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland.
authors.forename: Slawomira
authors.initials: S
authors.lastname: Kyrcz-Krzemien
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Markiewicz
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Dzierzak-Mietla
authors.affiliation: Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Wieslaw Wiktor
authors.initials: WW
authors.lastname: Jedrzejczak
authors.affiliation: L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Czajka
authors.affiliation: Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Mordak-Domagala
authors.affiliation: Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Lange
authors.affiliation: Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gronkowska
authors.affiliation: Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Warzocha
authors.affiliation: Department of Hematology and Transfusiology, Medical University of Gdansk, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Hellmann
authors.affiliation: Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kowalczyk
authors.affiliation: Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Drabko
authors.affiliation: Transplantation Centre, University Children's Hospital, Cracow, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gozdzik
authors.affiliation: Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Mizia
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006566:Herpesviridae Infections / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D012720:Severity of Illness Index; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors
chemical_list: D000961:Antilymphocyte Serum; D019653:Myeloablative Agonists; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein
keywords: Hematopoietic stem cell transplantation (HSCT); Herpes viruses; NOD2/CARD15 gene polymorphism; Sepsis