IRF8 allele associated with susceptibility to multiple sclerosis is associated with serum interferon α and serologic profile in systemic lupus erythematosus

Abstract

Objective: Alleles of IRF8 have been associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While interferon alpha (IFN-alpha) is thought to be causal in SLE, recombinant human IFN-alpha is used as a therapy in MS. We investigated whether the IRF8 alleles associated with these two diseases were associated with differences in serum IFN-alpha or serologic profile in a multi-ancestral cohort of SLE patients. Methods: The rs12444486 and rs17445836 single nucleotide polymorphisms (SNPs) in IRF8 (associated with SLE and MS respectively) were genotyped with Taqman primer-probe sets in 244 African-American and 137 European ancestry SLE patients. All patients had serum IFN-alpha and serology data available, and had been previously genotyped at SLE-risk SNPs in the IRF5 and IRF7 loci. Data from each ancestral background was analyzed separately initially, and combined in meta-analysis when associations were not significantly heterogeneous between ancestral backgrounds. Principal component analysis was used to control for proportional ancestry at the individual level. Results: The MS-associated rs17445836 G allele was associated with the presence of anti-dsDNA autoantibodies in SLE patients of both ancestral backgrounds [meta-analysis OR=2.01 (1.09-3.68), p=0.024]. The same allele was also associated with increased serum IFN-alpha activity in both ancestral backgrounds (metaanalysis p=0.017). There was no evidence for statistical interaction between rs17445836 G and SNPs in IRF5 and IRF7 which have been previously associated with anti-dsDNA in SLE patients. No significant associations were observed between the SLE-associated rs12444486 SNP and serum IFN-alpha or serologic profile. Conclusions: The rs17445836 G allele associated with susceptibility to MS was associated with anti-dsDNA antibodies and serum IFN-alpha in SLE patients of both African-American and European ancestry. This is interesting, given the therapeutic effect of IFN-alpha in MS patients, and the pathogenic effect of this same cytokine in SLE. Further exploration of the impact of the IRF8 locus upon in vivo IFN-alpha levels could provide insight into both diseases.