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oai:repisalud.isciii.es:20.500.12105/116842024-11-28T16:33:42Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_16938col_20.500.12105_16959col_20.500.12105_16984

00925njm 22002777a 4500 dc Sánchez-Maldonado, Jose Manuel author Moñiz-Díez, Ana author Ter Horst, Rob author Campa, Daniele author Cabrera-Serrano, Antonio José author Martínez-Bueno, Manuel author Garrido-Collado, María Del Pilar author Hernández-Mohedo, Francisca author Fernández-Puerta, Laura author López-Nevot, Miguel Ángel author Cunha, Cristina author González-Sierra, Pedro Antonio author Springer, Jan author Lackner, Michaela author Alcazar-Fuoli, Laura author Fianchi, Luana author Aguado, José María author Pagano, Livio author López-Fernández, Elisa author Clavero, Esther author Potenza, Leonardo author Luppi, Mario author Moratalla, Lucia author Solano, Carlos author Sampedro, Antonio author Cuenca-Estrella, Manuel author Lass-Flörl, Cornelia author PCRAGA Study Group author Canzian, Federico author Loeffler, Juergen author Li, Yang author Einsele, Hermann author Netea, Mihai G author Vázquez, Lourdes author Carvalho, Agostinho author Jurado, Manuel author Sainz, Juan author 2020-12-23 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. J Fungi (Basel). 2020 Dec 23;7(1):4. 10.3390/jof7010004 2309-608X Journal of fungi (Basel, Switzerland) 33374839 http://hdl.handle.net/20.500.12105/11684 B cells MAPKAPK2 TNFSF14 TNFSF4 TSLP Genetic susceptibility Invasive aspergillosis Monocytes Serum biomarkers 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