Document Detail


Association of IRF5 polymorphisms with activation of the interferon alpha pathway.
MedLine Citation:
PMID:  19854706     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: The genetic association of interferon regulatory factor 5 (IRF5) with systemic lupus erythematosus (SLE) susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, a study was undertaken to examine whether such genetic variation predisposes to activation of the interferon alpha (IFNalpha) pathway.
METHODS: Using a computer simulated approach, 14 single nucleotide polymorphisms (SNPs) and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFNalpha and IFN-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. IFN-inducible gene expression was assessed in LCLs from children with SLE in the presence and absence of IFNalpha stimulation.
RESULTS: The major alleles of IRF5 rs13242262 and rs2280714 were associated with increased IRF5 mRNA expression levels in the CEU, CHB+JPT and YRI samples. The minor allele of IRF5 rs10488631 was associated with increased IRF5, IFNalpha and IFN-inducible chemokine expression in CEU (p(c)=0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFNalpha and IFN-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of IFN-inducible genes in LCLs by IFNalpha.
CONCLUSIONS: SNPs of IRF5 in healthy individuals of a number of ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFNalpha and IFN-inducible chemokine expression. Identifying individuals genetically predisposed to increased IFN-inducible gene and chemokine expression may allow early detection of risk for SLE.
Authors:
Ornella J Rullo; Jennifer M P Woo; Hui Wu; Alice D C Hoftman; Paul Maranian; Brittany A Brahn; Deborah McCurdy; Rita M Cantor; Betty P Tsao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-10-23
Journal Detail:
Title:  Annals of the rheumatic diseases     Volume:  69     ISSN:  1468-2060     ISO Abbreviation:  Ann. Rheum. Dis.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-12     Completed Date:  2010-06-08     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  0372355     Medline TA:  Ann Rheum Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  611-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alleles
Chemokines / genetics
Gene Expression
Genotype
Humans
Interferon Regulatory Factors / genetics*,  metabolism
Interferon-alpha / genetics*
Lupus Erythematosus, Systemic / ethnology,  genetics
Polymorphism, Single Nucleotide*
RNA, Messenger / genetics
Grant Support
ID/Acronym/Agency:
5 K12 HC034510/HC/NHLBI NIH HHS; R01 AR043814/AR/NIAMS NIH HHS; R01 AR043814-12/AR/NIAMS NIH HHS; R01 AR43814/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Chemokines; 0/IRF5 protein, human; 0/Interferon Regulatory Factors; 0/Interferon-alpha; 0/RNA, Messenger
Comments/Corrections

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