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

Abstract

Background A major 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 & 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 dataset (∼1,200 subjects) and a replication dataset (>10,000 subjects) comprising European-descent individuals. Results Meta-analysis of 8p23 SNPs, with P<0.05 in both datasets, 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 2 ‘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.

STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus

“…Several studies have highlighted the 8p23 locus as a major SLE susceptibility region (44). Our study further expands the significance at this locus.…”

Cerebral small vessel disease genomics and its implications across the lifespan

“…ECHDC3, near a distinct locus (r 2 < 0.01) previously implicated in Alzheimer disease 63 . MN1, which previously has been causally related to familial meningiomas 64 , and XKR6, which has been associated with risk of systemic lupus erythematosus 65 .…”

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

“…High-density SNP analysis has identified and facilitated to focus on disease-associated loci where patients and healthy controls exhibit different frequencies of trait-associated alleles which are potential disease-causal variants or their proxies [47]. To date, about 100 SLE susceptibility loci have been identified, mostly in European and Asian populations [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86], explaining the heritability of SLE up to around 30% [74,75].…”