Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus.
OBJECTIVE
Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients.


METHODS
IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype.


RESULTS
IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression.


CONCLUSIONS
This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
Feng
Di
D
University of Medicine and Dentistry of New Jersey, Newark, NJ, USA.
Stone
Rivka C
RC
Eloranta
Maija-Leena
ML
Sangster-Guity
Niquiche
N
Nordmark
Gunnel
G
Sigurdsson
Snaevar
S
Wang
Chuan
C
Alm
Gunnar
G
Syvänen
Ann-Christine
AC
Rönnblom
Lars
L
Barnes
Betsy J
BJ
D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000097:blood; D007962:Leukocytes / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha