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
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AuthorSánchez Maldonado, José Manuel; Moñiz Díez, Ana; Cabrera Serrano, Antonio José; Martínez Bueno, Manuel; López Nevot, Miguel Ángel; Garrido Collado, María del Pilar; Hernández Mohedo, Francisca; Fernández Puerta, Laura; González Sierra, Pedro Antonio; Sainz Pérez, Juan
Invasive aspergillosisTNFSF4MAPKAPK2Genetic susceptibilityB cellsMonocytesSerum biomarkersTSLPTNFSF14
Sánchez-Maldonado, J.M.; Moñiz-Díez, A.; ter Horst, R.; Campa, D.; Cabrera-Serrano, A.J.; MartínezBueno, M.; Garrido-Collado, M.d.P.; Hernández-Mohedo, F.; FernándezPuerta, L.; López-Nevot, M.Á.; et al. 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. J. Fungi 2021, 7, 4. https:// dx.doi.org/10.3390/jof7010004
SponsorshipInstituto de Salud Carlos III PI17/02276; ERA-NET PathoGenoMics PIM2010EPA-00756 0315900A; Collaborative Research Center/Transregio 124 FungiNet; Portuguese Foundation for Science and Technology PTDC/SAU-SER/29635/2017 PTDC/MED-GEN/28778/2017 CEECIND/03628/2017 CEECIND/04058/2018; European Union (EU) 847507; La Caixa Foundation ID 100010434; Portuguese Foundation for Science and Technology LCF/PR/HP17/52190003; PI20/01845; PI12/02688
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 twostage 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.