Agnieszka Wójtowicz1, Mark S Gresnigt2, Thanh Lecompte3, Stephanie Bibert1, Oriol Manuel4, Leo A B Joosten2, Sina Rüeger5, Christoph Berger6, Katia Boggian7, Alexia Cusini8, Christian Garzoni9, Hans H Hirsch10, Maja Weisser10, Nicolas J Mueller11, Pascal R Meylan12, Jürg Steiger13, Zoltan Kutalik14, Manuel Pascual15, Christian van Delden3, Frank L van de Veerdonk2, Pierre-Yves Bochud1. 1. Infectious Diseases Service. 2. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Service of Transplantation Service of Infectious Diseases, University Hospitals of Geneva. 4. Infectious Diseases Service Transplantation Center, Department of Surgery. 5. Institute of Social and Preventive Medicine Swiss Institute of Bioinformatics, Lausanne. 6. Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zürich. 7. Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen. 8. Department of Infectious Diseases, Inselspital, Bern University Hospital and University of Bern. 9. Department of Infectious Diseases, Inselspital, Bern University Hospital and University of Bern Department of Internal Medicine. 10. Division of Infectious Diseases and Hospital Epidemiology. 11. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich. 12. Infectious Diseases Service Institute of Microbiology, University Hospital and University of Lausanne. 13. Clinic for Transplantation Immunology and Nephrology, University Hospital of Basel, Switzerland. 14. Infectious Diseases Service Swiss Institute of Bioinformatics, Lausanne. 15. Transplantation Center, Department of Surgery.
Abstract
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1Brs16944; P = .01 for DEFB1rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.
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