TY - JOUR
T1 - Impact of invasive aspergillosis occurring during first induction therapy on outcome of acute myeloid leukaemia (SEIFEM-12B study)
AU - Candoni, Anna
AU - Farina, Francesca
AU - Perruccio, Katia
AU - Di Blasi, Roberta
AU - Criscuolo, Marianna
AU - Cattaneo, Chiara
AU - Delia, Mario
AU - Zannier, Maria Elena
AU - Dragonetti, Giulia
AU - Fanci, Rosa
AU - Martino, Bruno
AU - Del Principe, Maria Ilaria
AU - Fianchi, Luana
AU - Vianelli, Nicola
AU - Chierichini, Anna
AU - Garzia, Mariagrazia
AU - Petruzzellis, Giuseppe
AU - Nadali, Gianpaolo
AU - Verga, Luisa
AU - Busca, Alessandro
AU - Pagano, Livio
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - AML
KW - SEIFEM
KW - induction chemotherapy
KW - invasive aspergillosis
KW - AML
KW - SEIFEM
KW - induction chemotherapy
KW - invasive aspergillosis
UR - https://publicatt.unicatt.it/handle/10807/167064
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85089654252&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85089654252&origin=inward
U2 - 10.1111/myc.13147
DO - 10.1111/myc.13147
M3 - Article
SN - 0933-7407
VL - 63
SP - 1094-1100-1100
JO - Mycoses
JF - Mycoses
IS - 10
ER -