title: Genetic susceptibility to severe asthma with fungal sensitization.
abstract: Severe asthma is problematic and its pathogenesis poorly understood. Fungal sensitization is common, and many patients with severe asthma with fungal sensitization (SAFS), used to denote this subgroup of asthma, respond to antifungal therapy. We have investigated 325 haplotype-tagging SNPs in 22 candidate genes previously associated with aspergillosis in patients with SAFS, with comparisons in atopic asthmatics and healthy control patients, of whom 47 SAFS, 279 healthy and 152 atopic asthmatic subjects were genotyped successfully. Significant associations with SAFS compared with atopic asthma included Toll-like receptor 3 (TLR3) (p = .009), TLR9 (p = .025), C-type lectin domain family seven member A (dectin-1) (p = .043), interleukin-10 (IL-10) (p = .0010), mannose-binding lectin (MBL2) (p = .007), CC-chemokine ligand 2 (CCL2) (2 SNPs, p = .025 and .041), CCL17 (p = .002), plasminogen (p = .049) and adenosine A2a receptor (p = .024). These associations differ from those found in ABPA in asthma, indicative of contrasting disease processes. Additional and broader genetic association studies in SAFS, combined with experimental work, are likely to contribute to our understanding of different phenotypes of problematic asthma.
authors.affiliation: Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, Manchester, UK.|Manchester Fungal Infection Group (MFIG), The University of Manchester, Manchester, UK.
authors.forename: N L
authors.identifier: http://orcid.org/0000-0003-0962-0268
authors.initials: NL
authors.lastname: Overton
authors.affiliation: Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Simpson
authors.affiliation: Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, Manchester, UK.|Manchester Fungal Infection Group (MFIG), The University of Manchester, Manchester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Bowyer
authors.affiliation: Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, Manchester, UK.|Manchester Fungal Infection Group (MFIG), The University of Manchester, Manchester, UK.
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000328:Adult; D000368:Aged; D001228:Aspergillosis / Q000150:complications / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D001249:Asthma / Q000150:complications / Q000235:genetics* / Q000382:microbiology* / Q000473:pathology; D054414:Chemokine CCL17 / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics; D008875:Middle Aged; D010958:Plasminogen / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D043705:Receptor, Adenosine A2A / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics; D000099181:Dectin-1
chemical_list: D054414:Chemokine CCL17; D018932:Chemokine CCL2; D016753:Interleukin-10; D037181:Lectins, C-Type; D037601:Mannose-Binding Lectin; D010958:Plasminogen; D043705:Receptor, Adenosine A2A; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; C106230:CCL17 protein, human; C111835:CCL2 protein, human; C546929:CLEC7A protein, human; D000099181:Dectin-1; C445619:MBL2 protein, human; C495344:TLR3 protein, human; C495371:TLR9 protein, human
keywords: allergy; asthma; disease association; disease association studies; genetics; polymorphism