Brief Report: IRF5 systemic lupus erythematosus risk haplotype is associated with asymptomatic serologic autoimmunity and progression to clinical autoimmunity in mothers of children with neonatal lupus

Abstract

Objective: Variation in the interferon regulatory factor 5 (IRF5) gene has been associated with risk of developing systemic lupus erythematosus (SLE), and this association is largely dependent upon anti-Ro autoantibodies. This study was undertaken to determine if the IRF5 genotype is associated with maternal diagnosis or progression of autoimmunity.

Methods: Genotyping of haplotype-tagging polymorphisms in IRF5 was performed in 93 subjects of European ancestry who were recruited to the Research Registry for Neonatal Lupus. All subjects had high-titer anti-Ro autoantibodies and had a child with neonatal lupus (NL); allele frequencies were compared to those in nonautoimmune controls. The mothers had SLE, Sjögren's syndrome (SS), or undifferentiated autoimmune syndrome (UAS), or were asymptomatic.

Results: The SLE risk haplotype of IRF5 was enriched in all anti-Ro-positive subjects except in those with SS (odds ratio [OR] 2.55, P = 8.8 × 10(-4) ). The SLE risk haplotype was even enriched in asymptomatic individuals with anti-Ro antibodies (OR 2.69, P = 0.019). The same haplotype was more prevalent in subjects who were initially asymptomatic but developed symptomatic SLE during followup (OR 5.83, P = 0.0024). Interestingly, SS was associated with 2 minor IRF5 haplotypes, and these same haplotypes were decreased in frequency in mothers with SLE and those with UAS.

Conclusion: The IRF5 SLE risk haplotype was associated with anti-Ro antibody positivity in asymptomatic individuals, as well as with progression to SLE in asymptomatic anti-Ro-positive individuals. SS in mothers of children with NL was associated with different IRF5 haplotypes. These data suggest that IRF5 polymorphisms play a role in serologic autoimmunity in humans and may promote the progression to clinical autoimmunity.

Conflict of interest statement

Financial Disclosures and Conflict of Interest: The authors report no financial conflict of interest.

Copyright © 2012 by the American College of Rheumatology.

Figures

Figure 1

IRF5 haplotype diagram and haplotype frequencies in the NL mothers. A. and B. show the pairwise correlations between SNPs as r-squared values for the NL mothers (A.) and controls (B.) respectively, with darker shading indicating a higher r-squared and thus a greater degree of correlation. C. and D. show the frequencies of the 5 major haplotypes observed in the NL mothers (C.) and controls (D.) respectively.