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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus
Journal of medical genetics, v 54(6), pp 381-389
01 Jun 2017
PMID: 28289186
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
BackgroundA 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 methodsIn 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.ResultsMeta-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.ConclusionsOur 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.
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Details
- Title
- Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus
- Creators
- F Yesim Demirci - University of PittsburghXingbin Wang - University of PittsburghDavid L Morris - King's College LondonEleanor Feingold - University of PittsburghSasha Bernatsky - McGill UniversityChristian Pineau - McGill UniversityAnn Clarke - University of CalgaryRosalind Ramsey-Goldman - Northwestern UniversitySusan Manzi - Allegheny Health NetworkTimothy J Vyse - King's College LondonM Ilyas Kamboh - University of Pittsburgh
- Publication Details
- Journal of medical genetics, v 54(6), pp 381-389
- Publisher
- British Medical Journal (BMJ)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- General Internal Medicine
- Web of Science ID
- WOS:000402366500002
- Scopus ID
- 2-s2.0-85020007367
- Other Identifier
- 991021933908804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity