Background/Purpose: Sjögren’s syndrome (SS) is a progressive autoimmune exocrinopathy characterized by symptoms of dry eyes and mouth present in 0.7-1% of Europeans. Dysregulation of interferon (IFN)-related pathways is well documented in SS and related autoimmune disorders, like systemic lupus erythematosus. To further characterize the expression of IFN-inducible genes in SS, we performed cis-expression quantitative trait loci (c-eQTL) analysis in SS cases to identify genetic variants regulating proximal IFN-regulated genes.

Methods: We first performed whole blood global gene expression profiling in 162 primary SS cases and 58 healthy controls of European ancestry. In total, 2410 genes were differentially expressed (DE) between SS cases and controls (3.49x10E-22≤q<0.05). Among pathways in which DE genes were identified, pathways involved in type I interferon-mediated signaling (31/70 genes; p=5.56x10E-14) were highly significant. The 31 genes were selected for use as phenotypic traits in c-eQTL analyses in 133 Caucasian SS patients through integration of gene expression data with genotypes from our SS genome-wide association study (GWAS, 424 cases / 2120 controls). Single nucleotide polymorphisms (SNPs) from GWAS data spanning 20kb flanking the target genes were tested for genetic association with expression levels by linear regression using Matrix-eQTL in the R Bioconductor suite.

Results: C-eQTL analysis identified SNPs within and flanking HLA-C (70 SNPs, 3.13x10E-9≤q<0.01) and OAS1 (26 SNPs, 6.29x10E-9≤q<0.01) that are significantly associated with gene expression levels. Alleles of HLA genes are well-documented risk factors for the development of autoimmune disorders, including SS. HLA-C belongs to the highly polymorphic MHC class I heavy chain molecule, and is a major independent genetic determinant of psoriasis and rheumatoid vasculitis. Our GWA study also showed associations of HLA-C eQTL with SS susceptibility with the top p=1.72x10E-22 in rs2844612. The association of rs2844612 with HLA-C expression levels is independent of other non-HLA-C SNPs in the MHC region, such as HLA-DRB1 and HLA-DQB1. Interestingly, the presence of both the risk alleles in HLA-C1 and its receptor killer cell immunoglobulin-like receptor (KIR)-2DS2 (2 extracellular domains with short cytoplasmic domain) is significantly associated with dry eye disease in a Han Chinese population. OAS1, or 2′,5′-oligoadenylate synthetase 1, is a critical component involved in the innate immune response to viral infection through RNA degradation and the inhibition of viral replication. Mutations in OAS1 have been associated with host susceptibility to viral infection. Evidence for association of the OAS1 SNP rs10774671, a splice-site polymorphism associated with multiple sclerosis and type 1 diabetes, increased from p=3.39x10E-3 in our SS GWAS to p=6.29x10E-9 in the c-eQTL analysis. 

Conclusion: Integration of results from genetic studies with gene expression data can help us to interpret downstream functional effects of SS susceptibility loci. These results provide promising novel candidate loci in and around HLA-C and OAS1 for future functional studies to better understand SS pathophysiology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cis-expression-quantitative-trait-loci-analysis-of-dysregulated-interferon-pathway-genes-identifies-hla-c-and-oas1-as-novel-candidates-for-susceptibility-to-sjogrens-syndrome/