Sanchez-Maldonado, Jose ManuelMoñiz-Diez, AnaTer Horst, RobCampa, DanieleCabrera-Serrano, Antonio JoseMartinez-Bueno, ManuelGarrido-Collado, Maria Del PilarHernandez-Mohedo, FranciscaFernandez-Puerta, LauraLopez-Nevot, Miguel AngelCunha, CristinaGonzalez-Sierra, Pedro AntonioSpringer, JanLackner, MichaelaAlcazar-Fuoli, LauraFianchi, LuanaAguado, Jose MariaPagano, LivioLopez-Fernandez, ElisaClavero, EstherPotenza, LeonardoLuppi, MarioMoratalla, LuciaSolano, CarlosSampedro, AntonioCuenca-Estrella, ManuelLass-Flörl, CorneliaPcraga Study Group,Canzian, FedericoLoeffler, JuergenLi, YangEinsele, HermannNetea, Mihai GVazquez, LourdesCarvalho, AgostinhoJurado, ManuelSainz, Juan2023-02-092023-02-092020-12-23Sánchez-Maldonado JM, Moñiz-Díez A, Ter Horst R, Campa D, Cabrera-Serrano AJ, Martínez-Bueno M, et al. Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium. J Fungi (Basel). 2020 Dec 23;7(1):4.http://hdl.handle.net/10668/16867Here, 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/B cellsMAPKAPK2TNFSF14TNFSF4TSLPgenetic susceptibilityinvasive aspergillosismonocytesserum biomarkersHumansPolymorphism, Single NucleotideThymic Stromal LymphopoietinTumor Necrosis Factor Ligand Superfamily Member 14MAP-kinase-activated kinase 2Allelesresearch article33374839open accessAlelosFosfotransferasasHumanosLinfopoyetina del estroma tímicoMiembro 14 de la Superfamilia de ligandos de factores de necrosisTumoralPolimorfismo de nucleótido simple10.3390/jof70100042309-608XPMC7823601https://www.mdpi.com/2309-608X/7/1/4/pdf?version=1609325928https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823601/pdf