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

Livio Pagano, Luana Fianchi, Jose Manuel Sánchez-Maldonado, Ana Moñiz-Díez, Rob Ter Horst, Daniele Campa, Antonio José Cabrera-Serrano, Manuel Martínez-Bueno, María Del Pilar Garrido-Collado, Francisca Hernández-Mohedo, Laura Fernández-Puerta, Miguel Ángel López-Nevot, Cristina Cunha, Pedro Antonio González-Sierra, Jan Springer, Michaela Lackner, Laura Alcazar-Fuoli, José María Aguado, Elisa López-Fernández, Esther ClaveroLeonardo Potenza, Mario Luppi, Lucia Moratalla, Carlos Solano, Antonio Sampedro, Manuel Cuenca-Estrella, Cornelia Lass-Flörl, Federico Canzian, Juergen Loeffler, Yang Li, Hermann Einsele, Mihai G. Netea, Lourdes Vázquez, Agostinho Carvalho, Manuel Jurado, Juan Sainz

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

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.
Lingua originaleEnglish
pagine (da-a)1-17
Numero di pagine17
RivistaJournal of Fungi
Volume7
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • B cells
  • Genetic susceptibility
  • Invasive aspergillosis
  • MAPKAPK2
  • TSLP
  • Serum biomarkers
  • TNFSF14
  • TNFSF4
  • Monocytes

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