Sánchez-Maldonado, Jose ManuelMoñiz-Díez, AnaTer Horst, RobCampa, DanieleCabrera-Serrano, Antonio JoséMartínez-Bueno, ManuelGarrido-Collado, María Del PilarHernández-Mohedo, FranciscaFernández-Puerta, LauraLópez-Nevot, Miguel ÁngelCunha, CristinaGonzález-Sierra, Pedro AntonioSpringer, JanLackner, MichaelaAlcazar-Fuoli, LauraFianchi, LuanaAguado, José MaríaPagano, LivioLópez-Fernández, ElisaClavero, EstherPotenza, LeonardoLuppi, MarioMoratalla, LuciaSolano, CarlosSampedro, AntonioCuenca-Estrella, ManuelLass-Flörl, CorneliaPCRAGA Study GroupCanzian, FedericoLoeffler, JuergenLi, YangEinsele, HermannNetea, Mihai GVázquez, LourdesCarvalho, AgostinhoJurado, ManuelSainz, Juan2021-01-272021-01-272020-12-23J Fungi (Basel). 2020 Dec 23;7(1):4.http://hdl.handle.net/20.500.12105/11684Here, 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.engVoRhttp://creativecommons.org/licenses/by/4.0/B cellsMAPKAPK2TNFSF14TNFSF4TSLPGenetic susceptibilityInvasive aspergillosisMonocytesSerum biomarkersAtribución 4.0 Internacional333748397110.3390/jof70100042309-608XJournal of fungi (Basel, Switzerland)open access