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Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

J Med Genet; 54(6): 381-389, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28289186


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 and , of which received 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). While most of these SNPs were related to previously implicated signals ( subregion), our results also revealed two 'new' SLE signals, including (6.06 × 10 ≤ meta p ≤ 4.88 × 10) and (meta p = 4.87 × 10) subregions that are located > 2 Mb upstream and ~ 0.3 Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative -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.