The 423Q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever.
OBJECTIVE
Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1beta or tumor necrosis factor alpha (TNFalpha). 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-kappaB 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 TNFalpha.


CONCLUSIONS
These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.
Ferretti
Massimo
M
Interdisciplinary Research Centre of Autoimmune Diseases, and University of Eastern Piedmont, Novara, Italy.
Gattorno
Marco
M
Chiocchetti
Annalisa
A
Mesturini
Riccardo
R
Orilieri
Elisabetta
E
Bensi
Thea
T
Sormani
Maria Pia
MP
Cappellano
Giuseppe
G
Cerutti
Elisa
E
Nicola
Stefania
S
Biava
Alessandra
A
Bardelli
Claudio
C
Federici
Silvia
S
Ceccherini
Isabella
I
Baldi
Maurizia
M
Santoro
Claudio
C
Dianzani
Irma
I
Martini
Alberto
A
Dianzani
Umberto
U
D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics / Q000378:metabolism; D010505:Familial Mediterranean Fever / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D054078:Mevalonate Kinase Deficiency / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
D016328:NF-kappa B; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020169:Caspases