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

Abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the <i>TNFSF4</i> and <i>MAPKAPK2</i> 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 <i>TNFSF4</i> _rs7526628T/T genotype had a significantly increased risk of developing IA (<i>p</i> = 0.00022). We also found that carriers of the <i>TNFSF4</i> _rs7526628T allele showed decreased serum levels of TNFSF14 protein (<i>p</i> = 0.0027), and that their macrophages had a decreased fungicidal activity (<i>p</i> = 0.048). In addition, we observed that each copy of the <i>MAPKAPK2</i> _rs12137965G allele increased the risk of IA by 60% (<i>p</i> = 0.0017), whereas each copy of the <i>MAPKAPK2</i> _rs17013271T allele was estimated to decrease the risk of developing the disease (<i>p</i> = 0.0029). Mechanistically, we found that carriers of the risk <i>MAPKAPK2</i> _rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (<i>p</i> = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (<i>p</i> = 0.00097). Finally, we also found that carriers of the protective <i>MAPKAPK2</i> _rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (<i>p</i> = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (<i>p</i> = 0.00018 and 0.00023). Altogether, these results suggest a role of the <i>TNFSF4 and MAPKAPK2</i> genes in determining IA risk.