Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.

Détails

ID Serval
serval:BIB_629937FEA425
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.
Périodique
New England Journal of Medicine
Auteur(s)
Bochud P.Y., Chien J.W., Marr K.A., Leisenring W.M., Upton A., Janer M., Rodrigues S.D., Li S., Hansen J.A., Zhao L.P., Aderem A., Boeckh M.
ISSN
1533-4406
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
359
Numéro
17
Pages
1766-1777
Langue
anglais
Résumé
BACKGROUND: Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants. METHODS: We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors. RESULTS: In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02). CONCLUSIONS: This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors.
Mots-clé
Adult, Analysis of Variance, Aspergillosis, Aspergillus fumigatus, Case-Control Studies, Female, Genetic Predisposition to Disease, Haplotypes, Hematopoietic Stem Cell Transplantation, Humans, Incidence, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Assessment, Toll-Like Receptor 4, Toll-Like Receptors, Transplantation, Homologous
Pubmed
Web of science
Création de la notice
10/02/2009 13:25
Dernière modification de la notice
20/08/2019 15:19
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