Autor(es):
Lupiañez, C. B. ; Canet, L. M. ; Carvalho, Agostinho Albérico Rodrigues de ; Alcazar-Fuolie, L. ; Springer, J. ; Lacknerg, M. ; Segura-Catena, J. ; Comino, A. ; Olmedo, C. ; Ríosa, R. ; Fernández-Montoya, A. ; Cuenca-Estrella, M. ; Solano, C. ; López-Nevotk, M. Á. ; Cunha, Cristina Amorim ; Coelho, Ana do Carmo Oliveira ; Villaescusal, T. ; Fianchin, L. ; Aguado, J. M. ; Paganon, L. ; López-Fernández, E. ; Potenza, L. ; Luppip, M. ; Lass-Flörlg, C. ; Loefflerf, J. ; Einselef, H. ; Vazquez, L. ; PCRAGA Study Group ; Jurado, M. ; Sainza, J.
Data: 2016
Identificador Persistente: http://hdl.handle.net/1822/46287
Origem: RepositóriUM - Universidade do Minho
Projeto/bolsa:
info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F96176%2F2013/PT;
Assunto(s): Ciências Médicas::Ciências da Saúde; Science & Technology
Descrição
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 were associated with an increased risk of IA (OR=1.92, 95%CI: 1.20-3.09 and OR=1.73, 1.06-2.81) whereas the IL12Brs3212227 and IFN?rs2069705 variants were significantly associated with a decreased risk of developing the infection (OR=0.60, 0.38-0.96 and OR=0.63, 0.41-0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFN?rs2069705 SNPs was stronger in allo-HSCT (OR=5.63, 1.20-3.09 and OR=0.24, 0.10-0.59) than in non-HSCT patients, suggesting that the presence of these SNPs may render patients more vulnerable to infection especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFN?rs2069705C allele showed a significantly increased macrophage-mediated neutralisation of fungal conidia (P=0.0003) and, under stimulation conditions, produced higher levels of IFN? mRNA (P=0.049) and IFN? and TNFa cytokines (PLPS-96h=0.057, PPHA-96h=0.036 and PLPS+PHA-96h=0.030 and PPHA -72h=0.045, PLPS+PHA-72h=0.018, PLPS-96h=0.058 and PLPS+PHA -96h=0.0058, respectively). 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 the disease (AUC=0.659 vs. AUC=0.564, PLR=5.2•10-4 and P50.000Perm=9.34•10-5). These findings suggest that the IFN?rs2069705 SNP influences the risk of IA and that predictive models built with IFN?, IL8, IL12p70 and VEGFa variants might be used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.
This study was supported by grants PI12/02688 from the Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), and the Collaborative Research Center/Transregio 124 FungiNet. C.C. is supported by the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BPD/96176/2013). This study also was supported by a donation of Consuelo González Moreno, an acute myeloid leukemia survivor. We thank Astella Pharma Inc. for supporting this work.
info:eu-repo/semantics/publishedVersion
