Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3′-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.
Highlights
The source of all cohorts used within this manuscript along with the analyses performed are presented as a flow diagram in Supplementary Fig. 1
Logistic regression revealed a synonymous variant, rs887369 (MAF = 0.24), to be the most significantly associated SNP (P = 3.34 × 10−7; OR = 1.43, 95% C.I = 1.23–1.66; Fig. 1a) and conditional analysis upon rs887369 showed no evidence of independent association signals (Fig. 1b)
The underrepresentation of genetic associations on the X chromosome in autoimmune disease is highly paradoxical given the prominent sex bias towards females and the increased density of immune related genes compared to the autosomes
Summary
Genetic refinement of the Xp21.2 SLE susceptibly locus. The source of all cohorts used within this manuscript along with the analyses performed are presented as a flow diagram in Supplementary Fig. 1. From our case/control data we have no evidence against the hypothesis that this association lies in an area of full inactivation To extend these analyses, we determined the odds ratios of the risk alleles in females and males separately. The risk haplotype increases expression of CXorf[21] in LCLs. As no protein-altering variants were identified through fine-mapping, we sought to establish whether the SLE risk alleles at CXorf[21] colocalised with cis-eQTLs for gene transcription. To study cis-eQTLs at the CXorf[21] locus, we employed two complementary methods of assessing the influence of the risk haplotype, tagged by rs887369, on the expression of genes within the Xp21.2 region: (1) using the hemizygosity of males to isolate the allelic effects; (2) removing females exhibiting strong evidence of extreme skewed XCI to a b.
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