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

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

Author:

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 FianchiJosé María AguadoLivio PaganoElisa López-FernándezEsther ClaveroLeonardo PotenzaMario LuppiLucia MoratallaCarlos SolanoAntonio SampedroManuel Cuenca-EstrellaCornelia Lass-FlörlPcraga Study GroupFederico CanzianJuergen LoefflerYang LiHermann Einsele Mihai G NeteaLourdes Vázquez Agostinho CarvalhoManuel JuradoJuan Sainz 

Date: 23 December 2020

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.

Keywords: B cells; MAPKAPK2; TNFSF14; TNFSF4; TSLP; genetic susceptibility; invasive aspergillosis; monocytes; serum biomarkers.

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