Polymorphisms within the ARNT2 and CX3CR1 genes are associated with the risk of developing invasive aspergillosis.

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Polymorphisms within the ARNT2 and CX3CR1 genes are associated with the risk of developing invasive aspergillosis.

Infect Immun. 2020 Jan 21;:

Authors: Lupiañez CB, Martínez-Bueno M, Sánchez-Maldonado JM, Badiola J, Cunha C, Springer J, Lackner M, Segura-Catena J, Canet LM, Alcazar-Fuoli L, López-Nevot MA, Fianchi L, Aguado JM, Pagano L, López-Fernández E, Alarcón-Riquelme M, Potenza L, Gonçalves SM, Luppi M, Moratalla L, Solano C, Sampedro A, González-Sierra P, Cuenca-Estrella M, Lagrou K, Maertens JA, Lass-Flörl C, Einsele H, Vazquez L, PCRAGA Study Group, Loeffler J, Ríos-Tamayo R, Carvalho A, Jurado M, Sainz J

Abstract
Invasive Aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplant 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 haematological patients. We genotyped selected SNPs in a cohort of 500 haematological patients (103 of those diagnosed with proven or probable IA) and we evaluated their association with the risk of developing IA. The association of the most interesting markers with IA risk was then validated in a replication population including 474 subjects (94 IA and 380 non-IA). 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 had a significantly increased risk of developing IA according to a log-additive model (PMeta=9.8•10-5; PMeta=1.5•10-4 and PMeta=7.9•10-5). Haplotype analysis also confirmed the association of the CX3CR1 AG CGG haplotype 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 whereas MDM from carriers of the ARNT2 rs1374213G and CX3CR1 rs9823718G or CX3CR1 rs7631529A alleles had deregulated immune responses against Aspergillus conidia. These results together with those from 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 ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development.

PMID: 31964743 [PubMed – as supplied by publisher]

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