Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium
Authors: Lupiañez C. B. , Canet L. M. , Carvalho A. , Alcazar-Fuoli L. , Springer J. , Lackner M. , Segura-Catena J. , Comino A. , Olmedo C. , Ríos R. , Fernández-Montoya A. , Cuenca-Estrella M. , Solano C. , López-Nevot M. Á. , Cunha C. , Oliveira-Coelho A. , Villaescusa T. , Fianchi L. , Aguado J. M. , Pagano L. , López-Fernández E. , Potenza L. , Luppi M. , Lass-Flörl C. , Loeffler J. , Einsele H. , Vazquez L. ,   the PCRAGA Study Group, Jurado M. , Sainz J. 
Published: December 2015

ABSTRACTRecent 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 theIL4Rrs2107356andIL8rs2227307SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09;IL8rs2227307OR, 1.73; 95% CI, 1.06 to 2.81), whereas theIL12Brs3212227andIFNγrs2069705variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227OR, 0.60; 95% CI, 0.38 to 0.96;IFNγrs2069705OR, 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 theIL4Rrs2107356andIFNγrs2069705SNPs was stronger in allo-HSCT (IL4Rrs2107356OR, 5.63; 95% CI, 1.20 to 3.09;IFNγrs2069705OR, 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 vitrostudies revealed that carriers of theIFNγrs2069705Callele 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 (Pvalue for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057;Pvalue 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 · 10−4andP50.000 permutation test= 9.34 · 10−5). These findings suggest that theIFNγrs2069705SNP influences the risk of IA and that predictive models built withIFNγ,IL8,IL12p70, andVEGFAvariants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.