title: Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium.
abstract: Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: C B
authors.initials: CB
authors.lastname: Lupiañez
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: L M
authors.initials: LM
authors.lastname: Canet
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Carvalho
authors.affiliation: Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Alcazar-Fuoli
authors.affiliation: Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Springer
authors.affiliation: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Lackner
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Segura-Catena
authors.affiliation: Experimental Research Unit, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Comino
authors.affiliation: Experimental Research Unit, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Olmedo
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Ríos
authors.affiliation: Blood Transfusion Regional Centre and Sectorial Tissue Bank, Granada, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fernández-Montoya
authors.affiliation: Mycology Reference Laboratory, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cuenca-Estrella
authors.affiliation: Hematology Department, Clinic University Hospital of Valencia, Valencia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Solano
authors.affiliation: Immunology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: M Á
authors.initials: MÁ
authors.lastname: López-Nevot
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Cunha
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Oliveira-Coelho
authors.affiliation: Hematology Department, University Hospital of Salamanca, Salamanca, Spain Hematology Department, Jiménez Díaz Foundation, Madrid, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Villaescusa
authors.affiliation: Istituto di Ematologia, Università Cattolica del S. Cuore, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fianchi
authors.affiliation: Unit of Infectious Diseases, Hospital Universitario 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Aguado
authors.affiliation: Istituto di Ematologia, Università Cattolica del S. Cuore, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pagano
authors.affiliation: Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: E
authors.initials: E
authors.lastname: López-Fernández
authors.affiliation: Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Potenza
authors.affiliation: Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Lass-Flörl
authors.affiliation: Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Loeffler
authors.affiliation: Universitätsklinikum Würzburg, Medizinische Klinik II, Würzburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Hematology Department, University Hospital of Salamanca, Salamanca, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Vazquez
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Jurado
authors.affiliation: Genomic Oncology Department, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain Hematology Department, Virgen de las Nieves University Hospital, Granada, Spain juan.sainz@genyo.es.
authors.forename: J
authors.initials: J
authors.lastname: Sainz
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001228:Aspergillosis / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016867:Immunocompromised Host / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics* / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C500879:IL12B protein, human; C504000:IL4R protein, human; D053762:Interleukin-12 Subunit p40; D053662:Interleukin-4 Receptor alpha Subunit; D016209:Interleukin-8; D007371:Interferon-gamma