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

Bochud, Pierre-Yves and Chien, Jason W and Marr, Kieren A and Leisenring, Wendy M and Upton, Arlo and Janer, Marta and Rodrigues, Stephanie D and Li, Sarah and Hansen, John A and Zhao, Lue Ping and Aderem, Alan and Boeckh, Michael (2008) Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. The New England journal of medicine, 359 (17). pp. 1766-1777. ISSN 1533-4406

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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.

Item Type: Article or Abstract
Additional Information: This article is available to subscribers only via the URL above.
DOI: 10.1056/NEJMoa0802629
PubMed ID: 18946062
PMCID: PMC2656610
Grant Numbers: P01 CA018029-33, P30 CA015704-34, U54 AI054523-019002, R01 AI051468-06, P01 AI033484-13, R01 HL087690-03, K23 HL069860-05, R01 HL088201-01A1, P41 RR003655-22
Keywords or MeSH Headings: Adult; Analysis of Variance; Aspergillosis/genetics; Aspergillus fumigatus; Case-Control Studies; Female; Genetic Predisposition to Disease; Haplotypes; Hematopoietic Stem Cell Transplantation/adverse effects/mortality; Humans; Incidence; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk Assessment; Toll-Like Receptor 4/genetics; Toll-Like Receptors/genetics; Transplantation, Homologous;
Subjects: Diseases > Bacterial and fungal diseases
Therapeutics > Transplantation > Stem Cell transplantation
Depositing User: Library Staff
Date Deposited: 03 Apr 2009 19:48
Last Modified: 11 Oct 2011 00:46

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