IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.
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.
Infectious Diseases Service.
Agnieszka
A
Wójtowicz
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Mark S
MS
Gresnigt
Service of Transplantation Service of Infectious Diseases, University Hospitals of Geneva.
Thanh
T
Lecompte
Infectious Diseases Service.
Stephanie
S
Bibert
Infectious Diseases Service Transplantation Center, Department of Surgery.
Oriol
O
Manuel
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Leo A B
LA
Joosten
Institute of Social and Preventive Medicine Swiss Institute of Bioinformatics, Lausanne.
Sina
S
Rüeger
Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zürich.
Christoph
C
Berger
Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen.
Katia
K
Boggian
Department of Infectious Diseases, Inselspital, Bern University Hospital and University of Bern.
Alexia
A
Cusini
Department of Infectious Diseases, Inselspital, Bern University Hospital and University of Bern Department of Internal Medicine.
Christian
C
Garzoni
Division of Infectious Diseases and Hospital Epidemiology.
Hans H
HH
Hirsch
Division of Infectious Diseases and Hospital Epidemiology.
Maja
M
Weisser
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich.
Nicolas J
NJ
Mueller
Infectious Diseases Service Institute of Microbiology, University Hospital and University of Lausanne.
Pascal R
PR
Meylan
Clinic for Transplantation Immunology and Nephrology, University Hospital of Basel, Switzerland.
Jürg
J
Steiger
Infectious Diseases Service Swiss Institute of Bioinformatics, Lausanne.
Zoltan
Z
Kutalik
Transplantation Center, Department of Surgery.
Manuel
M
Pascual
Service of Transplantation Service of Infectious Diseases, University Hospitals of Geneva.
Christian
C
van Delden
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Frank L
FL
van de Veerdonk
Infectious Diseases Service.
Pierre-Yves
PY
Bochud
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005658:Fungi / Q000302:isolation & purification*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D016377:Organ Transplantation / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D066027:Transplant Recipients; D023083:beta-Defensins / Q000235:genetics*
C406407:DEFB1 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D023083:beta-Defensins
aspergillosis; genetic susceptibility; innate immunity; interleukin-1 beta; invasive mold infections; single nucleotide polymorphism; solid organ transplant