TY - JOUR
T1 - 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
AU - Sánchez-Maldonado, Jose Manuel
AU - Moñiz-Díez, Ana
AU - Ter Horst, Rob
AU - Campa, Daniele
AU - Cabrera-Serrano, Antonio José
AU - Martínez-Bueno, Manuel
AU - Garrido-Collado, María Del Pilar
AU - Hernández-Mohedo, Francisca
AU - Fernández-Puerta, Laura
AU - López-Nevot, Miguel Ángel
AU - Cunha, Cristina
AU - González-Sierra, Pedro Antonio
AU - Springer, Jan
AU - Lackner, Michaela
AU - Alcazar-Fuoli, Laura
AU - Fianchi, Luana
AU - Aguado, José María
AU - Pagano, Livio
AU - López-Fernández, Elisa
AU - Clavero, Esther
AU - Potenza, Leonardo
AU - Luppi, Mario
AU - Moratalla, Lucia
AU - Solano, Carlos
AU - Sampedro, Antonio
AU - Cuenca-Estrella, Manuel
AU - Lass-Flörl, Cornelia
AU - Canzian, Federico
AU - Loeffler, Juergen
AU - Li, Yang
AU - Einsele, Hermann
AU - Netea, Mihai G.
AU - Vázquez, Lourdes
AU - Carvalho, Agostinho
AU - Jurado, Manuel
AU - Sainz, Juan
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - B cells
KW - Genetic susceptibility
KW - Invasive aspergillosis
KW - MAPKAPK2
KW - Monocytes
KW - Serum biomarkers
KW - TNFSF14
KW - TNFSF4
KW - TSLP
KW - B cells
KW - Genetic susceptibility
KW - Invasive aspergillosis
KW - MAPKAPK2
KW - Monocytes
KW - Serum biomarkers
KW - TNFSF14
KW - TNFSF4
KW - TSLP
UR - http://hdl.handle.net/10807/176223
U2 - 10.3390/jof7010004
DO - 10.3390/jof7010004
M3 - Article
SN - 2309-608X
VL - 7
SP - 1
EP - 17
JO - Journal of Fungi
JF - Journal of Fungi
ER -