| Contributors: |
Sanchez-Maldonado, J. M.; Moniz-Diez, A.; Ter Horst, R.; Campa, D.; Cabrera-Serrano, A. J.; Martinez-Bueno, M.; Garrido-Collado, M. P.; Hernandez-Mohedo, F.; Fernandez-Puerta, L.; Lopez-Nevot, M. A.; Cunha, C.; Gonzalez-Sierra, P. A.; Springer, J.; Lackner, M.; Alcazar-Fuoli, L.; Fianchi, L.; Aguado, J. M.; Pagano, L.; Lopez-Fernandez, E.; Clavero, E.; Potenza, L.; Luppi, M.; Moratalla, L.; Solano, C.; Sampedro, A.; Cuenca-Estrella, M.; Lass-Florl, C.; Canzian, F.; Loeffler, J.; Li, Y.; Einsele, H.; Netea, M. G.; Vazquez, L.; Carvalho, A.; Jurado, M.; Sainz, J. |
| Description: |
Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD-plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD-B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16-cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk. |