Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium

摘要

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 IL4R(rs2107356) and IL8(rs2227307) SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4R(rs2107356) odds ratio OR, 1.92; 95 confidence interval CI, 1.20 to 3.09; IL8(rs2227307) OR, 1.73; 95 CI, 1.06 to 2.81), whereas the IL12B(rs3212227) and IFN gamma(rs2069705) variants were significantly associated with a decreased risk of developing the infection (IL12B(rs3212227) OR, 0.60; 95 CI, 0.38 to 0.96; IFN gamma(rs2069705) 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 IL4R(rs2107356) and IFN gamma(rs2069705) SNPs was stronger in allo-HSCT (IL4R(rs2107356) OR, 5.63; 95 CI, 1.20 to 3.09; IFN gamma(rs2069705) 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 IFN gamma(rs2069705C) allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFN gamma) mRNA (P = 0.049) and IFN gamma and tumor necrosis factor alpha (TNF-alpha) 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 P-50.000 (permutation) (test) = 9.34 . 10(-5)). These findings suggest that the IFN gamma(rs2069705) SNP influences the risk of IA and that predictive models built with IFN gamma, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.