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-FAM167ABLK 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.
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