Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation
Open accessAbstract
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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Numerous single-nucleotide polymorphisms within human Toll-like receptors and C-type lectin receptors have been identified as risk factors for fungal disease.
“Numerous single-nucleotide polymorphisms (SNPs) within human TLRs (TLR1 [11], TLR4 [12–15], TLR6 [11], among others) and CLRs (Dectin-1—in particular the Y238X SNP [16–18]; DC-SIGN, mannose receptor and mannose-binding lectin [19–22]) have been identified as risk factors for fungal disease.”
From Race and ethnicity: Risk factors for fungal infections? (2023) · cites this paper as [12]
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- Authors
- 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.
- Affiliations
- Institute for Systems Biology (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-10-23
- Volume
- 359
- Issue
- 17
- Pages
- 1766-1777
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2656610
- OpenAlex
- W2087166943
- Cited by
- 453
- References
- 45
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 12 · 2023: 12 · 2022: 14 · 2021: 16 · 2020: 18 · 2019: 18 · 2018: 22 · 2017: 30 · 2016: 32 · 2015: 23 · 2014: 39 · 2013: 25 · 2012: 29
- FWCI
- 31.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL088201, K23HL069860, R01HL087690, HL69860, HL088201, HL87690)
- National Cancer Institute (CA18029, CA 15704+, P30CA015704, P01CA018029)
- National Institute of Allergy and Infectious Diseases (U54AI054523, AI33484, P01AI033484, AI051468, AI054523, R01AI051468, K24AI085118)
- National Center for Research Resources (RR-03655, P41RR003655)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- TLR4, TLR4 polymorphisms, invasive aspergillosis, hematopoietic stem cell transplantation, allogeneic stem cell transplantation, genetic susceptibility, fungal infection risk, TLR2, TLR3, TLR9, linkage disequilibrium, unrelated donor, related donors
- MeSH terms
- Adult, Analysis of Variance, Aspergillosis, Aspergillus fumigatus, Female, Haplotypes, Humans, Male, Middle Aged, Transplantation, Homologous, Linkage Disequilibrium, Incidence, Proportional Hazards Models, Case-Control Studies, Hematopoietic Stem Cell Transplantation, Risk Assessment, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Toll-Like Receptors, Toll-Like Receptor 4
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