title: 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.
authors.affiliation: Genomic Oncology Area, Genyo, Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research, Granada, Spain. juan.sainz@genyo.es
authors.forename: Juan
authors.initials: J
authors.lastname: Sainz
authors.forename: Carmen Belén
authors.initials: CB
authors.lastname: Lupiáñez
authors.forename: Juana
authors.initials: J
authors.lastname: Segura-Catena
authors.forename: Lourdes
authors.initials: L
authors.lastname: Vazquez
authors.forename: Rafael
authors.initials: R
authors.lastname: Ríos
authors.forename: Salvador
authors.initials: S
authors.lastname: Oyonarte
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Manuel
authors.initials: M
authors.lastname: Jurado
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001228:Aspergillosis / Q000235:genetics* / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005690:Galactose / Q000031:analogs & derivatives; D005838:Genotype; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D008172:Lung Diseases, Fungal / Q000235:genetics* / Q000382:microbiology*; D008297:Male; D008351:Mannans / Q000097:blood; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D012306:Risk; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D000099181:Dectin-1
chemical_list: D015815:Cell Adhesion Molecules; D005690:Galactose; D037181:Lectins, C-Type; D008351:Mannans; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D000099181:Dectin-1; C012990:galactomannan