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.

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.

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.

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.