Dectin-1 and DC-SIGN polymorphisms associated with invasive pulmonary Aspergillosis infection

PLoS One. 2012;7(2):e32273. doi: 10.1371/journal.pone.0032273. Epub 2012 Feb 27.

Abstract

The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1(rs3901533 T/T) and Dectin-1(rs7309123 G/G) genotypes and DC-SIGN(rs4804800 G), DC-SIGN(rs11465384 T), DC-SIGN(7248637 A) and DC-SIGN(7252229 C) alleles had a significantly increased risk of IPA infection (OR = 5.59 95%CI 1.37-22.77; OR = 4.91 95%CI 1.52-15.89; OR = 2.75 95%CI 1.27-5.95; OR = 2.70 95%CI 1.24-5.90; OR = 2.39 95%CI 1.09-5.22 and OR = 2.05 95%CI 1.00-4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1(rs3901533_T) allele and Dectin-1(rs7309123_G/G) genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1(rs7309123) polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aspergillosis / genetics*
  • Aspergillosis / microbiology*
  • Aspergillus fumigatus / metabolism*
  • Cell Adhesion Molecules / genetics*
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Genotype
  • Humans
  • Lectins, C-Type / genetics*
  • Lectins, C-Type / metabolism
  • Lung Diseases, Fungal / genetics*
  • Lung Diseases, Fungal / microbiology*
  • Male
  • Mannans / blood
  • Middle Aged
  • Odds Ratio
  • Polymerase Chain Reaction / methods
  • Polymorphism, Genetic*
  • Polymorphism, Single Nucleotide
  • Receptors, Cell Surface / genetics*
  • Risk

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • Mannans
  • Receptors, Cell Surface
  • dectin 1
  • galactomannan