Publicação

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

Detalhes bibliográficos
Resumo:	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><sub>rs7526628T/T</sub> genotype had a significantly increased risk of developing IA (<i>p</i> = 0.00022). We also found that carriers of the <i>TNFSF4</i><sub>rs7526628T</sub> 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><sub>rs12137965G</sub> allele increased the risk of IA by 60% (<i>p</i> = 0.0017), whereas each copy of the <i>MAPKAPK2</i><sub>rs17013271T</sub> 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><sub>rs12137965G</sub> 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><sub>rs17013271T</sub> 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.
Autores principais:	Sánchez-Maldonado, Jose Manuel
Outros Autores:	Moñiz-Díez, Ana; ter Horst, Rob; Campa, Daniele; Cabrera-Serrano, Antonio José; Martínez-Bueno, Manuel; Garrido-Collado, María del Pilar; Hernández-Mohedo, Francisca; Fernández-Puerta, Laura; López-Nevot, Miguel Ángel; Cunha, Cristina; González-Sierra, Pedro Antonio; Springer, Jan; Lackner, Michaela; Alcazar-Fuoli, Laura; Fianchi, Luana; Aguado, José María; Pagano, Livio; López-Fernández, Elisa; Clavero, Esther; Potenza, Leonardo; Luppi, Mario; Moratalla, Lucia; Solano, Carlos; Sampedro, Antonio; Cuenca-Estrella, Manuel; Lass-Flörl, Cornelia; PCRAGA Study Group,; Canzian, Federico; Loeffler, Juergen; Li, Yang; Einsele, Hermann; Netea, Mihai G.; Vázquez, Lourdes; Carvalho, Agostinho; Jurado, Manuel; Sainz, Juan
Assunto:	invasive aspergillosis TNFSF4 MAPKAPK2 genetic susceptibility B cells monocytes serum biomarkers TSLP TNFSF14 Ciências Médicas::Ciências da Saúde
Ano:	2021
País:	Portugal
Tipo de documento:	artigo
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade do Minho
Idioma:	inglês
Origem:	RepositóriUM - Universidade do Minho

Descrição
Resumo:	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><sub>rs7526628T/T</sub> genotype had a significantly increased risk of developing IA (<i>p</i> = 0.00022). We also found that carriers of the <i>TNFSF4</i><sub>rs7526628T</sub> 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><sub>rs12137965G</sub> allele increased the risk of IA by 60% (<i>p</i> = 0.0017), whereas each copy of the <i>MAPKAPK2</i><sub>rs17013271T</sub> 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><sub>rs12137965G</sub> 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><sub>rs17013271T</sub> 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.