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.
Jose Manuel Sánchez-MaldonadoAna Moñiz-DíezRob Ter HorstDaniele CampaAntonio José Cabrera-SerranoManuel Martínez-BuenoMaría Del Pilar Garrido-ColladoFrancisca Hernández-MohedoLaura Fernández-PuertaMiguel Ángel López-NevotCristina CunhaPedro Antonio González-SierraJan SpringerMichaela LacknerLaura Alcazar-FuoliLuana FianchiJose María AguadoLivio PaganoElisa López-FernándezEsther ClaveroLeonardo PotenzaMario LuppiLucia MoratallaCarlos SolanoAntonio SampedroManuel Cuenca-EstrellaCornelia Lass-Flörlnull Pcraga Study GroupFrederico CanzianJuergen LoefflerYang LiHermann EinseleMihai G NeteaLourdes VázquezAgostinho CarvalhoManuel JuradoJuan SainzPublished in: Journal of fungi (Basel, Switzerland) (2020)
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.