| Title: |
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. |
| Authors: |
Manuel Sánchez-Maldonado, Jose, Moñiz-Díez, Ana, Horst, Rob ter, Campa, Daniele, José Cabrera-Serrano, Antonio, Martínez-Bueno, Manuel, del Pilar Garrido-Collado, María, Hernández-Mohedo, Francisca, Fernández-Puerta, Laura, Ángel López-Nevot, Miguel, Cunha, Cristina, Antonio González-Sierra, Pedro, Springer, Jan, Lackner, Michaela, Alcazar-Fuoli, Laura, Fianchi, Luana, María Aguado, José, Pagano, Livio, López-Fernández, Elisa, Clavero, Esther |
| Source: |
Journal of Fungi; Jan2021, Vol. 7 Issue 1, p1-17, 17p |
| Subject Terms: |
ASPERGILLOSIS, SINGLE nucleotide polymorphisms, MACROPHAGES, MITOGEN-activated protein kinases, B cells |
| 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
