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
Sánchez-Maldonado J, Moñiz-Díez A, Ter Horst R, Campa D, Cabrera-Serrano A, Martínez-Bueno M, Garrido-Collado M, Hernández-Mohedo F, Fernández-Puerta L, López-Nevot M, Cunha C, González-Sierra P, Springer J, Lackner M, Alcazar-Fuoli L, Fianchi L, Aguado J, Pagano L, López-Fernández E, Clavero E, Potenza L, Luppi M, Moratalla L, Solano C, Sampedro A, Cuenca-Estrella M, Lass-Flörl C, Pcraga Study Group, Canzian F, Loeffler J, Li Y, Einsele H, Netea M, Vázquez L, Carvalho A, Jurado M, Sainz J
Published in
Journal of fungi (Basel, Switzerland): Volume 7, Issue 1, Page 4
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 TNFSF4 (rs7526628T/T) genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4 (rs7526628T) 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 MAPKAPK2 (rs12137965G) allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2 (rs17013271T) allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2 (rs12137965G) 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 MAPKAPK2 (rs17013271T) 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.
Open in PubMed