Journal of Fungi (Dec 2020)

Polymorphisms within the <i>TNFSF4</i> and <i>MAPKAPK2</i> Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium

  • 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,
  • Luana Fianchi,
  • José María Aguado,
  • Livio Pagano,
  • Elisa López-Fernández,
  • Esther Clavero,
  • Leonardo Potenza,
  • Mario Luppi,
  • Lucia Moratalla,
  • Carlos Solano,
  • Antonio Sampedro,
  • Manuel Cuenca-Estrella,
  • Cornelia Lass-Flörl,
  • PCRAGA Study Group,
  • Federico Canzian,
  • Juergen Loeffler,
  • Yang Li,
  • Hermann Einsele,
  • Mihai G. Netea,
  • Lourdes Vázquez,
  • Agostinho Carvalho,
  • Manuel Jurado,
  • Juan Sainz

DOI
https://doi.org/10.3390/jof7010004
Journal volume & issue
Vol. 7, no. 1
p. 4

Abstract

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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.

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