title: Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.
abstract: A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5  Mb) located at 8p23. Initially implicated genes includedFAM167A-BLKandXKR6, of whichBLKreceived major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported.
  
  
  
  In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4  Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~1200  subjects) and a replication data set (> 10 000  subjects) comprising European-descent individuals.
  
  
  
  Meta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10-8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLKsubregion), our results also revealed two 'new' SLE signals, includingSGK223-CLDN23-MFHAS1(6.06 × 10-9≤ meta p ≤ 4.88 × 10-8) andCTSB(meta p = 4.87 × 10-8) subregions that are located > 2 Mb upstream and ~ 0.3  Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putativecis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background.
  
  
  
  Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA.
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Xingbin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, UK.
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.affiliation: Division of Rheumatology, Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Sasha
authors.initials: S
authors.lastname: Bernatsky
authors.affiliation: Division of Rheumatology, Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Pineau
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, Canada.
authors.forename: Ann
authors.initials: A
authors.lastname: Clarke
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, USA.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.affiliation: Department of Medicine, Lupus Center of Excellence, Allegheny Health Network, Pittsburgh, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Manzi
authors.affiliation: Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Kamboh
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics
keywords: 
  BLK
  ; 8p23; Lupus; SLE; inversion