title: IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
abstract: OBJECTIVE
  High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.
  
  
  METHODS
  1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African-American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.
  
  
  RESULTS
  In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9×10(-14) for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African-American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African-American subjects and absent in African patients with SLE.
  
  
  CONCLUSIONS
  The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population. These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness and are likely pathogenic in SLE.
authors.affiliation: Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois 60637, USA. tniewold@medicine.bsd.uchicago.edu
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Silvia N
authors.initials: SN
authors.lastname: Kariuki
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Franek
authors.forename: Akaash A
authors.initials: AA
authors.lastname: Kumar
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: Kenaz
authors.initials: K
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Walker
authors.forename: Stan
authors.initials: S
authors.lastname: Kamp
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Frost
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Wong
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: Mohammed
authors.initials: M
authors.lastname: Tikly
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Petri
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Diane L
authors.initials: DL
authors.lastname: Kamen
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Mary K
authors.initials: MK
authors.lastname: Crow
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
mesh_terms: D001741:Black or African American / Q000235:genetics; D000974:Antibodies, Antinuclear / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D004247:DNA / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D016898:Interferon-alpha / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; C035356:SS-A antibodies; D004247:DNA
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