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 Sánchez Maldonado, José Manuel Moñiz Díez, Ana Cabrera Serrano, Antonio José Martínez Bueno, Manuel López Nevot, Miguel Ángel Garrido Collado, María del Pilar Hernández Mohedo, Francisca Fernández Puerta, Laura González Sierra, Pedro Antonio Sáinz Pérez, Juan Invasive aspergillosis TNFSF4 MAPKAPK2 Genetic susceptibility B cells Monocytes Serum biomarkers TSLP TNFSF14 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 twostage 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. 2021-02-16T07:41:45Z 2021-02-16T07:41:45Z 2020 info:eu-repo/semantics/article Sánchez-Maldonado, J.M.; Moñiz-Díez, A.; ter Horst, R.; Campa, D.; Cabrera-Serrano, A.J.; MartínezBueno, M.; Garrido-Collado, M.d.P.; Hernández-Mohedo, F.; FernándezPuerta, L.; López-Nevot, M.Á.; 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 2021, 7, 4. https:// dx.doi.org/10.3390/jof7010004 http://hdl.handle.net/10481/66587 10.3390/jof7010004 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI