Article Text

PDF

IRF8 allele associated with susceptibility to multiple sclerosis is associated with serum interferon α and serologic profile in systemic lupus erythematosus
  1. Beverly S Franek1,
  2. Silvia N Kariuki1,
  3. Jasmine Arrington1,
  4. Rachel A Mikolaitis2,
  5. Meenakshi Jolly2,
  6. Tammy O Utset1,
  7. Mary Zervou3,
  8. Dimitrios T Boumpas3,
  9. George Goulielmos3,
  10. Timothy B Niewold1
  1. 1Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
  2. 2Section of Rheumatology, Rush University Medical Center, Chicago, Illinois, USA
  3. 3Internal Medicine and Rheumatology, Clinical Immunology and Allergy, University of Crete Medical School, Heraklion, Greece

Abstract

Objective Alleles of IRF8 have been associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While interferon α (IFN-α) is thought to be causal in SLE, recombinant human IFN-α 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-α 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. We studied 548 SLE patients (258 African-American, 147 European-American, and 143 Cretan) and 526 matched controls (298 African-American, 117 European-American, and 111 Cretan). All patients had serum IFN-α 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 analysed 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 in logistic regressions.

Results In case-control meta-analysis, we observed a stronger and more consistent cross-ancestral background association between IRF8 and SLE at the MS-associated rs17445836 SNP than at the previously reported SLE-associated rs1244486 SNP (OR=0.66, p=2.7×10−3, Cochran's Q=0.80). 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-α activity in both ancestral backgrounds (meta-analysis 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-α or serologic profile.

Conclusions The rs17445836 G allele associated with susceptibility to MS was associated with SLE, and with anti-dsDNA antibodies and serum IFN-α in SLE patients of both African-American and European ancestry. This is interesting, given the therapeutic effect of IFN-α 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-α levels should provide insight into both diseases.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.