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Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus
  1. F Yesim Demirci1,
  2. Xingbin Wang1,
  3. David L Morris2,
  4. Eleanor Feingold1,
  5. Sasha Bernatsky3,
  6. Christian Pineau3,
  7. Ann Clarke4,
  8. Rosalind Ramsey-Goldman5,
  9. Susan Manzi6,
  10. Timothy J Vyse2,
  11. M Ilyas Kamboh1
  1. 1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA
  2. 2 Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, UK
  3. 3 Division of Rheumatology, Department of Medicine, McGill University, Montreal, Canada
  4. 4 Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, Canada
  5. 5 Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, USA
  6. 6 Department of Medicine, Lupus Center of Excellence, Allegheny Health Network, Pittsburgh, USA
  1. Correspondence to Dr F Yesim Demirci, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; fyd1{at}
  2. and M Ilyas Kamboh, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; kamboh{at}


Background 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 included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported.

Objective and methods 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.

Results 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-BLK subregion), our results also revealed two ‘new’ SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10−9 ≤ meta p ≤ 4.88 × 10−8) and CTSB (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 putative cis-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.

Conclusions 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.

  • Lupus
  • SLE
  • 8p23
  • BLK
  • inversion

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  • Contributors FYD and MIK planned the study, conducted research, evaluated/interpreted the data/results and drafted the manuscript. XW and EF conducted research, performed statistical analysis and/or provided statistical expertise and evaluated/interpreted the data/results. SB, CP, AC, RR-G and SM conducted research, provided the samples/data and clinical expertise. DLM and TJV conducted research, performed the analyses in the replication sample and provided the replication data and expertise. All authors contributed to the research and to the critical review of the manuscript.

  • Funding This work was supported by grants from the US NIH (HL092397, HL088648, AR057028, AR046588, AR057338, HD066139, AR002138, AR030692, AR064464 and TR000150) and by grants from Wellcome Trust (Ref 085492) and Arthritis Research UK (Ref 19289).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.