PT - JOURNAL ARTICLE AU - Demirci, F Yesim AU - Wang, Xingbin AU - Morris, David L AU - Feingold, Eleanor AU - Bernatsky, Sasha AU - Pineau, Christian AU - Clarke, Ann AU - Ramsey-Goldman, Rosalind AU - Manzi, Susan AU - Vyse, Timothy J AU - Ilyas Kamboh, M TI - Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus AID - 10.1136/jmedgenet-2016-104247 DP - 2017 Jun 01 TA - Journal of Medical Genetics PG - 381--389 VI - 54 IP - 6 4099 - http://jmg.bmj.com/content/54/6/381.short 4100 - http://jmg.bmj.com/content/54/6/381.full SO - J Med Genet2017 Jun 01; 54 AB - 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.