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

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.
AuthorsJuan Sainz, Carmen Belén Lupiáñez, Juana Segura-Catena, Lourdes Vazquez, Rafael Ríos, Salvador Oyonarte, Kari Hemminki, Asta Försti, Manuel Jurado
JournalPloS one (PLoS One) Vol. 7 Issue 2 Pg. e32273 ( 2012) ISSN: 1932-6203 [Electronic] United States
PMID22384201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Lectins, C-Type
  • Mannans
  • Receptors, Cell Surface
  • dectin 1
  • galactomannan
  • Galactose
Topics
  • Adolescent
  • Adult
  • Aged
  • Aspergillosis (genetics, microbiology)
  • Aspergillus fumigatus (metabolism)
  • Cell Adhesion Molecules (genetics)
  • Enzyme-Linked Immunosorbent Assay (methods)
  • Female
  • Galactose (analogs & derivatives)
  • Genotype
  • Humans
  • Lectins, C-Type (genetics, metabolism)
  • Lung Diseases, Fungal (genetics, microbiology)
  • Male
  • Mannans (blood)
  • Middle Aged
  • Odds Ratio
  • Polymerase Chain Reaction (methods)
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Receptors, Cell Surface (genetics)
  • Risk

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