6533b857fe1ef96bd12b463d

RESEARCH PRODUCT

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

Juan SainzPedro Antonio González-sierraLaura Fernández-puertaFrancisca Hernández-mohedoAntonio José Cabrera-serranoLivio PaganoManuel Martínez-buenoEsther ClaveroCarlos SolanoHermann EinseleLuana FianchiManuel Cuenca-estrellaYang LiYang LiAntonio SampedroMaría Del Pilar Garrido-colladoRob Ter HorstElisa López-fernándezLourdes VazquezAgostinho CarvalhoLeonardo PotenzaMario LuppiJuergen LoefflerManuel JuradoLucía MoratallaLaura Alcazar-fuoliJosé María AguadoFederico CanzianMiguel A. López-nevotMichaela LacknerDaniele CampaJose Manuel Sánchez-maldonadoJan SpringerCornelia Lass-flörlAna Moñiz-díezCristina CunhaMihai G. NeteaMihai G. Netea

subject

Microbiology (medical)Thymic stromal lymphopoietinCiências Médicas::Ciências da Saúde:Ciências da Saúde [Ciências Médicas]lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]Context (language use)Single-nucleotide polymorphismPlant ScienceCD38BiologyMonocytes03 medical and health sciencesAll institutes and research themes of the Radboud University Medical Center0302 clinical medicineGenotypeB cells; MAPKAPK2; TNFSF14; TNFSF4; TSLP; genetic susceptibility; invasive aspergillosis; monocytes; serum biomarkersB cells; Genetic susceptibility; Invasive aspergillosis; MAPKAPK2; Monocytes; Serum biomarkers; TNFSF14; TNFSF4; TSLPGenetic predispositionGenetic susceptibilityddc:610Allelelcsh:QH301-705.5Ecology Evolution Behavior and Systematics030304 developmental biology0303 health sciencesB cellsTNFSF14Science & TechnologyTNFSF4Case-control studyMAPKAPK2Serum biomarkers<i>TNFSF4</i>3. Good healthSettore MED/15 - MALATTIE DEL SANGUE<i>MAPKAPK2</i>lcsh:Biology (General)TSLPImmunologyInvasive aspergillosis030215 immunology

description

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.

yearjournalcountryeditionlanguage
2020-12-23
10.3390/jof7010004http://hdl.handle.net/10807/176223