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

Livio Pagano, Luana Fianchi, Jose Manuel Sánchez-Maldonado, Ana Moñiz-Díez, Rob Ter Horst, Daniele Campa, Antonio José Cabrera-Serrano, Manuel Martínez-Bueno, María Del Pilar Garrido-Collado, Francisca Hernández-Mohedo, Laura Fernández-Puerta, Miguel Ángel López-Nevot, Cristina Cunha, Pedro Antonio González-Sierra, Jan Springer, Michaela Lackner, Laura Alcazar-Fuoli, José María Aguado, Elisa López-Fernández, Esther ClaveroLeonardo Potenza, Mario Luppi, Lucia Moratalla, Carlos Solano, Antonio Sampedro, Manuel Cuenca-Estrella, Cornelia Lass-Flörl, null Pcraga Study Group, Federico Canzian, Juergen Loeffler, Yang Li, Hermann Einsele, Mihai G Netea, Lourdes Vázquez, Agostinho Carvalho, Manuel Jurado, Juan Sainz

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

nvasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2 rs1374213G, CX3CR1 rs7631529A, and CX3CR1 rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [P Meta] = 9.8 · 10-5, P Meta = 1.5 · 10-4, and P Meta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2 rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2 rs1374213G and CX3CR1 rs9823718G or CX3CR1 rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1 rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.
Lingua originaleEnglish
pagine (da-a)4-10
Numero di pagine7
RivistaJournal of Fungi
Volume7
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • B cells
  • MAPKAPK2
  • TNFSF14
  • TNFSF4
  • TSLP
  • genetic susceptibility
  • invasive aspergillosis
  • monocytes
  • serum biomarkers

Fingerprint

Entra nei temi di ricerca di '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'. Insieme formano una fingerprint unica.

Cita questo