title: Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus.
abstract: OBJECTIVE
  The overexpression of interferon (IFN)-inducible genes is a prominent feature of systemic lupus erythematosus (SLE); it serves as a marker for active and more severe disease, and is also observed in other autoimmune and inflammatory conditions. This study was undertaken to investigate the genetic variations responsible for sustained activation of IFN-responsive genes in SLE.
  
  
  METHODS
  We systematically evaluated association of SLE with a total of 1,754 IFN pathway-related genes, including IFN-inducible genes known to be differentially expressed in SLE patients and their direct regulators. We used a 3-stage study design in which 2 cohorts (total of 939 SLE cases and 3,398 controls) were analyzed independently and jointly for association with SLE, and the results were adjusted for the number of comparisons.
  
  
  RESULTS
  A total of 15,166 single-nucleotide polymorphisms (SNPs) passed all quality control filters; 305 of these SNPs demonstrated replicated association with SLE in both cohorts. Nine variants were further genotyped for confirmation in an average of 1,316 independent SLE cases and 3,215 independent controls. Association with SLE was confirmed for several genes, including those for the transmembrane receptor CD44 (CD44 [rs507230]; P = 3.98 × 10⁻¹²), the cytokine pleiotrophin (PTN [rs919581]; P = 5.38 × 10⁻⁴), the heat-shock protein DnaJ (DNAJA1 [rs10971259]; P = 6.31 × 10⁻³), and the nuclear import protein karyopherin α1 (KPNA [rs6810306]; P = 4.91 × 10⁻²).
  
  
  CONCLUSIONS
  This study expands the number of candidate genes that have been shown to be associated with SLE and highlights potential of pathway-based approaches for gene discovery. Identification of the causal alleles will help elucidate the molecular mechanisms responsible for activation of the IFN system in SLE.
authors: Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA. pramos@wfubmc.edu
authors: Paula S
authors: PS
authors: Ramos
authors: Adrienne H
authors: AH
authors: Williams
authors: Julie T
authors: JT
authors: Ziegler
authors: Mary E
authors: ME
authors: Comeau
authors: Richard T
authors: RT
authors: Guy
authors: Christopher J
authors: CJ
authors: Lessard
authors: He
authors: H
authors: Li
authors: Jeffrey C
authors: JC
authors: Edberg
authors: Raphael
authors: R
authors: Zidovetzki
authors: Lindsey A
authors: LA
authors: Criswell
authors: Patrick M
authors: PM
authors: Gaffney
authors: Deborah Cunninghame
authors: DC
authors: Graham
authors: Robert R
authors: RR
authors: Graham
authors: Jennifer A
authors: JA
authors: Kelly
authors: Kenneth M
authors: KM
authors: Kaufman
authors: Elizabeth E
authors: EE
authors: Brown
authors: Graciela S
authors: GS
authors: Alarcón
authors: Michelle A
authors: MA
authors: Petri
authors: John D
authors: JD
authors: Reveille
authors: Gerald
authors: G
authors: McGwin
authors: Luis M
authors: LM
authors: Vilá
authors: Rosalind
authors: R
authors: Ramsey-Goldman
authors: Chaim O
authors: CO
authors: Jacob
authors: Timothy J
authors: TJ
authors: Vyse
authors: Betty P
authors: BP
authors: Tsao
authors: John B
authors: JB
authors: Harley
authors: Robert P
authors: RP
authors: Kimberly
authors: Marta E
authors: ME
authors: Alarcón-Riquelme
authors: Carl D
authors: CD
authors: Langefeld
authors: Kathy L
authors: KL
authors: Moser
mesh_terms: D000483:Alleles; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D006239:Haplotypes; D006801:Humans; D007372:Interferons / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D007372:Interferons