PMID- 18946062 OWN - NLM STAT- MEDLINE DCOM- 20081030 LR - 20191210 IS - 1533-4406 (Electronic) IS - 0028-4793 (Print) IS - 0028-4793 (Linking) VI - 359 IP - 17 DP - 2008 Oct 23 TI - Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. PG - 1766-77 LID - 10.1056/NEJMoa0802629 [doi] 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. CI - 2008 Massachusetts Medical Society FAU - Bochud, Pierre-Yves AU - Bochud PY AD - Institute for Systems Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. FAU - Chien, Jason W AU - Chien JW FAU - Marr, Kieren A AU - Marr KA FAU - Leisenring, Wendy M AU - Leisenring WM FAU - Upton, Arlo AU - Upton A FAU - Janer, Marta AU - Janer M FAU - Rodrigues, Stephanie D AU - Rodrigues SD FAU - Li, Sarah AU - Li S FAU - Hansen, John A AU - Hansen JA FAU - Zhao, Lue Ping AU - Zhao LP FAU - Aderem, Alan AU - Aderem A FAU - Boeckh, Michael AU - Boeckh M LA - eng GR - HL088201/HL/NHLBI NIH HHS/United States GR - R01 HL087690-03/HL/NHLBI NIH HHS/United States GR - CA18029/CA/NCI NIH HHS/United States GR - P41 RR003655/RR/NCRR NIH HHS/United States GR - P01 CA018029-33/CA/NCI NIH HHS/United States GR - P01 CA018029/CA/NCI NIH HHS/United States GR - P30 CA015704/CA/NCI NIH HHS/United States GR - AI054523/AI/NIAID NIH HHS/United States GR - P41 RR003655-22/RR/NCRR NIH HHS/United States GR - K24 AI085118/AI/NIAID NIH HHS/United States GR - K23 HL069860-05/HL/NHLBI NIH HHS/United States GR - AI33484/AI/NIAID NIH HHS/United States GR - R01 HL088201-01A1/HL/NHLBI NIH HHS/United States GR - R01 HL088201/HL/NHLBI NIH HHS/United States GR - HL87690/HL/NHLBI NIH HHS/United States GR - HL69860/HL/NHLBI NIH HHS/United States GR - K23 HL069860/HL/NHLBI NIH HHS/United States GR - RR03655/RR/NCRR NIH HHS/United States GR - U54 AI054523-019002/AI/NIAID NIH HHS/United States GR - P01 AI033484/AI/NIAID NIH HHS/United States GR - CA15704/CA/NCI NIH HHS/United States GR - R01 AI051468-06/AI/NIAID NIH HHS/United States GR - P30 CA015704-34/CA/NCI NIH HHS/United States GR - P01 AI033484-13/AI/NIAID NIH HHS/United States GR - AI051468/AI/NIAID NIH HHS/United States GR - U54 AI054523/AI/NIAID NIH HHS/United States GR - R01 HL087690/HL/NHLBI NIH HHS/United States GR - R01 AI051468/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Validation Study PL - United States TA - N Engl J Med JT - The New England journal of medicine JID - 0255562 RN - 0 (TLR4 protein, human) RN - 0 (Toll-Like Receptor 4) RN - 0 (Toll-Like Receptors) SB - IM CIN - N Engl J Med. 2008 Oct 23;359(17):1836-8. PMID: 18946070 CIN - N Engl J Med. 2009 Feb 5;360(6):634; author reply 635-6. PMID: 19196681 CIN - N Engl J Med. 2009 Feb 5;360(6):634-5; author reply 635-6. PMID: 19202579 CIN - N Engl J Med. 2009 Feb 5;360(6):635; author reply 635-6. PMID: 19202580 MH - Adult MH - Analysis of Variance MH - Aspergillosis/*genetics MH - Aspergillus fumigatus MH - Case-Control Studies MH - Female MH - Genetic Predisposition to Disease MH - Haplotypes MH - *Hematopoietic Stem Cell Transplantation/adverse effects/mortality MH - Humans MH - Incidence MH - Linkage Disequilibrium MH - Male MH - Middle Aged MH - *Polymorphism, Single Nucleotide MH - Proportional Hazards Models MH - Risk Assessment MH - Toll-Like Receptor 4/*genetics MH - Toll-Like Receptors/genetics MH - Transplantation, Homologous PMC - PMC2656610 MID - NIHMS84845 EDAT- 2008/10/24 09:00 MHDA- 2008/10/31 09:00 PMCR- 2009/04/23 CRDT- 2008/10/24 09:00 PHST- 2008/10/24 09:00 [pubmed] PHST- 2008/10/31 09:00 [medline] PHST- 2008/10/24 09:00 [entrez] PHST- 2009/04/23 00:00 [pmc-release] AID - 359/17/1766 [pii] AID - 10.1056/NEJMoa0802629 [doi] PST - ppublish SO - N Engl J Med. 2008 Oct 23;359(17):1766-77. doi: 10.1056/NEJMoa0802629.