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

Pierre Yves Bochud, Jason W. Chien, Kieren Marr, Wendy M. Leisenring, Arlo Upton, Marta Janer, Stephanie D. Rodrigues, Sarah Li, John A. Hansen, Ping Zhao Lue, Alan Aderem, Michael Boeckh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1766-1777
Number of pages12
JournalNew England Journal of Medicine
Volume359
Issue number17
DOIs
StatePublished - Oct 23 2008
Externally publishedYes

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Toll-Like Receptor 4
Aspergillosis
Stem Cell Transplantation
Unrelated Donors
Haplotypes
Tissue Donors
Confidence Intervals
Transplants
Genes
Validation Studies
Toll-Like Receptors
Odds Ratio
Cytomegalovirus
Single Nucleotide Polymorphism
Toll-Like Receptor 3
Toll-Like Receptor 9
Toll-Like Receptor 2
Linkage Disequilibrium
Regression Analysis
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bochud, P. Y., Chien, J. W., Marr, K., Leisenring, W. M., Upton, A., Janer, M., ... Boeckh, M. (2008). Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. New England Journal of Medicine, 359(17), 1766-1777. https://doi.org/10.1056/NEJMoa0802629

Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. / Bochud, Pierre Yves; Chien, Jason W.; Marr, Kieren; Leisenring, Wendy M.; Upton, Arlo; Janer, Marta; Rodrigues, Stephanie D.; Li, Sarah; Hansen, John A.; Lue, Ping Zhao; Aderem, Alan; Boeckh, Michael.

In: New England Journal of Medicine, Vol. 359, No. 17, 23.10.2008, p. 1766-1777.

Research output: Contribution to journalArticle

Bochud, PY, Chien, JW, Marr, K, Leisenring, WM, Upton, A, Janer, M, Rodrigues, SD, Li, S, Hansen, JA, Lue, PZ, Aderem, A & Boeckh, M 2008, 'Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation', New England Journal of Medicine, vol. 359, no. 17, pp. 1766-1777. https://doi.org/10.1056/NEJMoa0802629
Bochud, Pierre Yves ; Chien, Jason W. ; Marr, Kieren ; Leisenring, Wendy M. ; Upton, Arlo ; Janer, Marta ; Rodrigues, Stephanie D. ; Li, Sarah ; Hansen, John A. ; Lue, Ping Zhao ; Aderem, Alan ; Boeckh, Michael. / Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. In: New England Journal of Medicine. 2008 ; Vol. 359, No. 17. pp. 1766-1777.
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abstract = "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.",
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T1 - Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation

AU - Bochud, Pierre Yves

AU - Chien, Jason W.

AU - Marr, Kieren

AU - Leisenring, Wendy M.

AU - Upton, Arlo

AU - Janer, Marta

AU - Rodrigues, Stephanie D.

AU - Li, Sarah

AU - Hansen, John A.

AU - Lue, Ping Zhao

AU - Aderem, Alan

AU - Boeckh, Michael

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N2 - 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.

AB - 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.

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