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 included <i>FAM167A-BLK</i> and <i>XKR6</i>, of which <i>BLK</i> 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 (<i>~</i> 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 (<i>XKR6-FAM167A-BLK</i> subregion), our results also revealed two 'new' SLE signals, including <i>SGK223-CLDN23-MFHAS1</i> (6.06 × 10^-9 ≤ meta p ≤ 4.88 × 10^-8) and <i>CTSB</i> (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 <i>cis</i>-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.