1. 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
- Author
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Sanchez-Maldonado, J. M., Moniz-Diez, A., Ter Horst, R., Campa, D., Cabrera-Serrano, A. J., Martinez-Bueno, M., Garrido-Collado, M. P., Hernandez-Mohedo, F., Fernandez-Puerta, L., Lopez-Nevot, M. A., Cunha, C., Gonzalez-Sierra, P. A., Springer, J., Lackner, M., Alcazar-Fuoli, L., Fianchi, L., Aguado, J. M., Pagano, L., Lopez-Fernandez, E., Clavero, E., Potenza, L., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Cuenca-Estrella, M., Lass-Florl, C., Canzian, F., Loeffler, J., Li, Y., Einsele, H., Netea, M. G., Vazquez, L., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Sanchez-Maldonado, J. M., Moniz-Diez, A., Ter Horst, R., Campa, D., Cabrera-Serrano, A. J., Martinez-Bueno, M., Garrido-Collado, M. P., Hernandez-Mohedo, F., Fernandez-Puerta, L., Lopez-Nevot, M. A., Cunha, C., Gonzalez-Sierra, P. A., Springer, J., Lackner, M., Alcazar-Fuoli, L., Fianchi, L., Aguado, J. M., Pagano, L., Lopez-Fernandez, E., Clavero, E., Potenza, L., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Cuenca-Estrella, M., Lass-Florl, C., Canzian, F., Loeffler, J., Li, Y., Einsele, H., Netea, M. G., Vazquez, L., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)
- 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.
- Published
- 2021