%0 Journal Article
%A Sanchez-Maldonado, Jose Manuel
%A Moñiz-Diez, Ana
%A Ter Horst, Rob
%A Campa, Daniele
%A Cabrera-Serrano, Antonio Jose
%A Martinez-Bueno, Manuel
%A Garrido-Collado, Maria Del Pilar
%A Hernandez-Mohedo, Francisca
%A Fernandez-Puerta, Laura
%A Lopez-Nevot, Miguel Angel
%A Cunha, Cristina
%A Gonzalez-Sierra, Pedro Antonio
%A Springer, Jan
%A Lackner, Michaela
%A Alcazar-Fuoli, Laura
%A Fianchi, Luana
%A Aguado, Jose Maria
%A Pagano, Livio
%A Lopez-Fernandez, Elisa
%A Clavero, Esther
%A Potenza, Leonardo
%A Luppi, Mario
%A Moratalla, Lucia
%A Solano, Carlos
%A Sampedro, Antonio
%A Cuenca-Estrella, Manuel
%A Lass-Flörl, Cornelia
%A Pcraga Study Group,
%A Canzian, Federico
%A Loeffler, Juergen
%A Li, Yang
%A Einsele, Hermann
%A Netea, Mihai G
%A Vazquez, Lourdes
%A Carvalho, Agostinho
%A Jurado, Manuel
%A Sainz, Juan
%T 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.
%D 2020
%U http://hdl.handle.net/10668/16867
%X 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.
%K B cells
%K MAPKAPK2
%K TNFSF14
%K TNFSF4
%K TSLP
%K genetic susceptibility
%K invasive aspergillosis
%K monocytes
%K serum biomarkers
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