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Association of IRF5 polymorphisms with activation of the Interferon-alpha pathway
  1. Ornella J Rullo1,*,
  2. Jennifer M P Woo1,
  3. Hui Wu1,
  4. Alice D C Hoftman2,
  5. Paul Maranian1,
  6. Brittany A Brahn1,
  7. Deborah McCurdy1,
  8. Rita Cantor1,
  9. Betty Tsao1
  1. 1 UCLA School of Medicine, United States;
  2. 2 Div of Pediatric Rheumatology, Children's Hospital Orange County, United States
  1. Correspondence to: Ornella J Rullo, Pediatric Rheumatology, UCLA, 10833 Le Conte Ave MDCC 1st Floor, Los Angeles, CA 90272, United States; orullo{at}


Objective: Genetic association of Interferon Regulatory Factor 5 (IRF5) with SLE susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, we examined whether such genetic variation predisposes to activation of the Interferon-α) (IFN-α) pathway.

Methods: In this in silico approach, 14 SNPs and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFN--α), and interferon-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. Interferon-inducible gene expression was assessed in LCLs from pediatric SLE patients in the presence and absence of IFN-α) 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, IFN-α) and interferon-inducible chemokine expression in CEU (pc = 0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFN-α) and interferon-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of interferon-inducible genes in LCLs by IFN-α).

Conclusions: SNPs of IRF5 in healthy individuals of multiple ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFN-α) and interferon-inducible chemokine expression. Identifying individuals genetically predisposed to increased interferon-inducible gene and chemokine expression may allow early detection of risk for SLE.

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