The Y238X stop codon polymorphism in the human β-glucan receptor dectin-1 and susceptibility to invasive aspergillosis.
BACKGROUND
Dectin-1 is the major receptor for fungal β-glucans on myeloid cells. We investigated whether defective Dectin-1 receptor function, because of the early stop codon polymorphism Y238X, enhances susceptibility to invasive aspergillosis (IA) in at-risk patients.


METHODS
Association of Dectin-1 Y238X polymorphism with occurrence and clinical course of IA was evaluated in 71 patients who developed IA post hematopoietic stem cell transplantation (HSCT) and in another 21 non-HSCT patients with IA. The control group consisted of 108 patients who underwent HSCT. Functional studies were performed to investigate consequences of the Y238X Dectin-1 polymorphism.


RESULTS
The Y238X allele frequency was higher in non-HSCT patients with IA (19.0% vs 6.9%-7.7%; P < .05). Heterozygosity for Y238X polymorphism in HSCT recipients showed a trend toward IA susceptibility (odds ratio, 1.79; 95% CI, .77-4.19; P = .17) but did not influence clinical course of IA. Functional assays revealed that although peripheral blood mononuclear cells with defective Dectin-1 function due to Y238X responded less efficiently to Aspergillus, corresponding macrophages showed adequate response to Aspergillus.


CONCLUSIONS
Dectin-1 Y238X heterozygosity has a limited influence on susceptibility to IA and may be important in susceptible non-HSCT patients. This is partly attributable to redundancy inherent in the innate immune system. Larger studies are needed to confirm these findings.
Department of Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.
Louis Y A
LY
Chai
Mark G J
MG
de Boer
Walter J F M
WJ
van der Velden
Theo S
TS
Plantinga
Annemiek B
AB
van Spriel
Cor
C
Jacobs
Constantijn J M
CJ
Halkes
Alieke G
AG
Vonk
Nicole M
NM
Blijlevens
Jaap T
JT
van Dissel
Peter J
PJ
Donnelly
Bart-Jan
BJ
Kullberg
Johan
J
Maertens
Mihai G
MG
Netea
D000328:Adult; D001228:Aspergillosis / Q000235:genetics* / Q000276:immunology*; D001530:Belgium; D016022:Case-Control Studies; D018388:Codon, Terminator / Q000235:genetics*; D016207:Cytokines; D005260:Female; D005434:Flow Cytometry; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006579:Heterozygote; D006801:Humans; D037181:Lectins, C-Type; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D047071:beta-Glucans / Q000378:metabolism; D000099181:Dectin-1
D018388:Codon, Terminator; D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047071:beta-Glucans; D000099181:Dectin-1
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