Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/11684
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, Jose Manuel | Moñiz-Díez, Ana | Ter Horst, Rob | Campa, Daniele | Cabrera-Serrano, Antonio José | Martínez-Bueno, Manuel | Garrido-Collado, María Del Pilar | Hernández-Mohedo, Francisca | Fernández-Puerta, Laura | López-Nevot, Miguel Ángel | Cunha, Cristina | González-Sierra, Pedro Antonio | Springer, Jan | Lackner, Michaela | Alcazar-Fuoli, Laura ISCIII | Fianchi, Luana | Aguado, José María | Pagano, Livio | López-Fernández, Elisa | Clavero, Esther | Potenza, Leonardo | Luppi, Mario | Moratalla, Lucia | Solano, Carlos | Sampedro, Antonio | Cuenca-Estrella, Manuel ISCIII | Lass-Flörl, Cornelia | Pcraga Study Group, null | Canzian, Federico | Loeffler, Juergen | Li, Yang | Einsele, Hermann | Netea, Mihai G | Vázquez, Lourdes | Carvalho, Agostinho | Jurado, Manuel | Sainz, Juan
J Fungi (Basel) . 2020 Dec 23;7(1):4.
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.
B cells | MAPKAPK2 | TNFSF14 | TNFSF4 | TSLP | genetic susceptibility | invasive aspergillosis | monocytes | serum biomarkers
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