The 423q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever

Massimo Ferretti, Marco Gattorno, Annalisa Chiocchetti, Riccardo Mesturini, Elisabetta Orilieri, Thea Bensi, Maria Pia Sormani, Giuseppe Cappellano, Elisa Cerutti, Stefania Nicola, Alessandra Biava, Claudio Bardelli, Silvia Federici, Isabella Ceccherini, Maurizia Baldi, Claudio Santoro, Irma Dianzani, Alberto Martini, Umberto Dianzani

Research output: Contribution to journalArticle

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Abstract

Objective. Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1β or tumor necrosis factor α (TNFα). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-κB signaling, both of which are processes that influence the development of inflammatory cells. Methods. The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. Results. Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFα. Conclusion. These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.

Original languageEnglish
Pages (from-to)3476-3484
Number of pages9
JournalArthritis and Rheumatism
Volume60
Issue number11
DOIs
Publication statusPublished - Nov 2009

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Monocytes
Fever
Apoptosis
Genes
Familial Mediterranean Fever
Caspase 9
Hereditary Autoinflammatory Diseases
Mevalonate Kinase Deficiency
Cryopyrin-Associated Periodic Syndromes
Tumor Necrosis Factor-alpha
X-Linked Inhibitor of Apoptosis Protein
X-Linked Genes
Tumor Necrosis Factor Receptors
Amino Acid Substitution
Caspases
Interleukin-1
Gene Library
Causality
Lipopolysaccharides
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

The 423q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever. / Ferretti, Massimo; Gattorno, Marco; Chiocchetti, Annalisa; Mesturini, Riccardo; Orilieri, Elisabetta; Bensi, Thea; Sormani, Maria Pia; Cappellano, Giuseppe; Cerutti, Elisa; Nicola, Stefania; Biava, Alessandra; Bardelli, Claudio; Federici, Silvia; Ceccherini, Isabella; Baldi, Maurizia; Santoro, Claudio; Dianzani, Irma; Martini, Alberto; Dianzani, Umberto.

In: Arthritis and Rheumatism, Vol. 60, No. 11, 11.2009, p. 3476-3484.

Research output: Contribution to journalArticle

Ferretti, M, Gattorno, M, Chiocchetti, A, Mesturini, R, Orilieri, E, Bensi, T, Sormani, MP, Cappellano, G, Cerutti, E, Nicola, S, Biava, A, Bardelli, C, Federici, S, Ceccherini, I, Baldi, M, Santoro, C, Dianzani, I, Martini, A & Dianzani, U 2009, 'The 423q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever', Arthritis and Rheumatism, vol. 60, no. 11, pp. 3476-3484. https://doi.org/10.1002/art.24905
Ferretti, Massimo ; Gattorno, Marco ; Chiocchetti, Annalisa ; Mesturini, Riccardo ; Orilieri, Elisabetta ; Bensi, Thea ; Sormani, Maria Pia ; Cappellano, Giuseppe ; Cerutti, Elisa ; Nicola, Stefania ; Biava, Alessandra ; Bardelli, Claudio ; Federici, Silvia ; Ceccherini, Isabella ; Baldi, Maurizia ; Santoro, Claudio ; Dianzani, Irma ; Martini, Alberto ; Dianzani, Umberto. / The 423q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever. In: Arthritis and Rheumatism. 2009 ; Vol. 60, No. 11. pp. 3476-3484.
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T1 - The 423q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever

AU - Ferretti, Massimo

AU - Gattorno, Marco

AU - Chiocchetti, Annalisa

AU - Mesturini, Riccardo

AU - Orilieri, Elisabetta

AU - Bensi, Thea

AU - Sormani, Maria Pia

AU - Cappellano, Giuseppe

AU - Cerutti, Elisa

AU - Nicola, Stefania

AU - Biava, Alessandra

AU - Bardelli, Claudio

AU - Federici, Silvia

AU - Ceccherini, Isabella

AU - Baldi, Maurizia

AU - Santoro, Claudio

AU - Dianzani, Irma

AU - Martini, Alberto

AU - Dianzani, Umberto

PY - 2009/11

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N2 - Objective. Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1β or tumor necrosis factor α (TNFα). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-κB signaling, both of which are processes that influence the development of inflammatory cells. Methods. The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. Results. Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNFα. Conclusion. These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.

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