title: Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation.
abstract: Invasive aspergillosis (IA) is a significant cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Previous studies have reported an association between IA development and single nucleotide polymorphisms (SNPs), but many SNPs have not been replicated in a separate cohort. The presence of a positive serum galactomannan assay (SGM+) has also been associated with a worse prognosis in patients with IA, and genetic determinants in this subset of patients have not been systematically studied. The study cohort included 2609 HCT recipients and their donor pairs: 483 with proven/probable IA (183 SGM+) and 2126 with no IA by standard criteria. Of 25 SNPs previously published, we analyzed 20 in 14 genes that passed quality control. Samples were genotyped via microarray, and SNPs that could not be genotyped were imputed. The primary aim was to replicate SNPs associated with proven/probable IA at 2 years; secondary goals were to explore the associations using an end point of SGM+ IA or proven/probable IA using a different genetic model or time to IA (3 months vs 2 years) compared with the original study. Two SNPs in 2 genes (PTX3,CLEC7a) were replicated. Thirteen SNPs in 9 genes had an association atP≤ .05 using the secondary aims (PTX3,CLEC7a,CD209,CXCL10,TLR6,S100B,IFNG,PLG,TNFR1), with hazard ratios ranging from 1.2 to 3.29. Underlying genetic differences can influence development of IA following HCT. Identification of genetic predispositions to IA could have important implications in donor screening, risk stratification of recipients, monitoring, and prophylaxis.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Fisher
authors.affiliation: Infectious Disease Service, Department of Medicine, and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.affiliation: Division of Public Health Sciences, and.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Fan
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA.
authors.forename: David M
authors.initials: DM
authors.lastname: Levine
authors.affiliation: Division of Public Health Sciences, and.
authors.forename: Lu Ping
authors.initials: LP
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
authors.forename: Edus H
authors.initials: EH
authors.lastname: Warren
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.|Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boeckh
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
authors.forename: John A
authors.initials: JA
authors.lastname: Hansen
mesh_terms: D000328:Adult; D001228:Aspergillosis / Q000209:etiology* / Q000235:genetics*; D002097:C-Reactive Protein / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000683:Serum Amyloid P-Component / Q000235:genetics; D000099153:Pentraxins; D000099181:Dectin-1
chemical_list: D002097:C-Reactive Protein; D037181:Lectins, C-Type; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C546929:CLEC7A protein, human; D000099181:Dectin-1