Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation

Cynthia E. Fisher, Tobias M. Hohl, Wenhong Fan, Barry E. Storer, David M. Levine, Lu Ping Zhao, Paul J. Martin, Edus H. Warren, Michael Boeckh and John A. Hansen

Key Points

  • Two SNPs in PTX3 and CLEC7a previously associated with development of proven or probable invasive aspergillosis were validated.

  • Thirteen SNPs in 9 genes were associated at P ≤ .05 with development of IA using a different genetic model than the original study.


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 at P ≤ .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.

  • Submitted October 13, 2016.
  • Accepted February 27, 2017.
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