title: A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE.
abstract: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10⁻⁵), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.
authors.affiliation: Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Sandling
authors.forename: Sophie
authors.initials: S
authors.lastname: Garnier
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Catharina
authors.initials: C
authors.lastname: Eriksson
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Mälarstig
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.forename: Gunnar
authors.initials: G
authors.lastname: Alm
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
mesh_terms: D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D007370:Interferon Type I / Q000276:immunology*; D016209:Interleukin-8 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics; D013548:Sweden; D044465:White People / Q000235:genetics
chemical_list: C508606:CXCL8 protein, human; D007370:Interferon Type I; D016209:Interleukin-8; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051550:I-kappa B Kinase; C496565:IKBKE protein, human