ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2772

Identification Of a Sjögren’s Syndrome-Associated Variant That Influences OAS1 Isoform Switching

He Li1,2, John A. Ice3, Jennifer A. Kelly3, Indra Adrianto1, Stuart B. Glenn3, Kimberly S. Hefner4, Evan G. Vista5, Donald U. Stone6, Raj Gopalakrishnan7, Glen D. Houston8, David M. Lewis9, Michael Rohrer7, Pamela Hughes7, John B. Harley10,11, Courtney G. Montgomery3, James Chodosh12, James A. Lessard13, Juan-Manuel Anaya14, Barbara M. Segal15, Nelson L. Rhodus16, Lida Radfar2, R. Hal Scofield17, Christopher J. Lessard3,18 and Kathy L. Sivils1, 1Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 2University of Oklahoma Health Sciences Center, Oklahoma City, OK, 3Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 4Hefner Eye Care and Optical Center, Oklahoma City, OK, 5Rheumatology and Clinical Immunology, University of Santo Tomas, Taguig City, Philippines, 6Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 7Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN, 8Collage of Denistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 9College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 10Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 11US Department of Veterans Affairs Medical Center, Cincinnati, OH, 12Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 13Valley Bone and Joint Clinic, Grand Forks, ND, 14Center for Autoimmune Diseases Research (CREA), Universidad del Rosario., Bogota, Colombia, 15Rheumatology, Hennepin County Medical Center, Minneapolis, MN, 16University of Minnesota, Minneapolis, MN, 17Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 18Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: Sjögren's Syndrome: Basic Science

Session Type: Abstract Submissions (ACR)

Background/Purpose: Sjögren’s syndrome (SS) is a common, progressive autoimmune exocrinopathy characterized by symptoms of dry eyes and mouth present in 0.7-1% of the European population. Our previous gene expression profiling (GEP) study has demonstrated overexpression of transcripts induced by interferons (IFN) in SS patients. Here, we sought to identify and characterize underlying genetic contributions to dysregulation of IFN pathways in SS.

Methods: IFN signature genes of interest were selected from GEP studies performed in 180 SS cases and 73 controls using Illumina HumanWG-6 v3.0 microarray data and evaluated for cis-expression quantitative trait loci (eQTL) in 222 subjects by integration with genome-wide association study (GWAS) data. Gene splicing patterns were evaluated using microarray data and supplemented with RNA-sequencing (RNA-seq) performed in 57 SS cases and 27 controls on the Illumina platform. Transcripts measured by RNA-seq were reconstructed using Cufflinks and the relative abundance of isoforms was compared across samples according to genotypes for loci of interest.

Results: GEP showed that OAS1, an IFN-inducible gene involved in inhibition of virus replication, was significantly overexpressed in SS patients. Multiple cis-eQTL were identified in OAS1 with the most significant peaking at rs10774671, strengthening prior evidence of this variant for disease association (P=6×10-3) obtained in our large GWAS dataset consisting of 395 cases and 1975 controls. We further replicated this genetic association in an independent set of 648 cases and 2927 controls followed by meta-analysis using a weighted Z score (Pmeta=9×10-6; OR=0.79). The rs10774671 A allele conferred risk, is a splice site variant located at the intersection between intron-5 and exon-6, and thus may switch the primary normal isoform, p46, to various alternatives. To characterize functional impact of this variant, we evaluated alternative splicing events using both microarray and RNA-seq data. Variation in splicing was detectable by a microarray probe that specifically recognizes a truncated form of OAS1 (p42). Both microarray and RNA-seq showed that the risk allele A, which demolishes the splicing consensus sequence, was correlated with higher expression of p42 (Pmicro=2×10-16 and Pseq=1×10-15). RNA-seq results also showed correlation of the A risk allele with higher proportions of p48 and p44 isoforms (P=9×10-8 and P=4×10-4, respectively), but a lower expression of the functionally normal isoform, p46 (P=4×10-30). 

Conclusion: We identified OAS1 as a novel candidate SS locus that confers risk through a functional eQTL at rs10774671. This splice site variant switches the primary p46 isoform to multiple alternatives with decreased OAS1 enzyme activity potentially contributing to reduced ability to inhibit viral replication. These results indicate the risk allele may cause vulnerability to viral infection that contributes to SS susceptibility.

Disclosure:

H. Li,
None;

J. A. Ice,
None;

J. A. Kelly,
None;

I. Adrianto,
None;

S. B. Glenn,
None;

K. S. Hefner,
None;

E. G. Vista,
None;

D. U. Stone,
None;

R. Gopalakrishnan,
None;

G. D. Houston,
None;

D. M. Lewis,
None;

M. Rohrer,
None;

P. Hughes,
None;

J. B. Harley,
None;

C. G. Montgomery,
None;

J. Chodosh,
None;

J. A. Lessard,
None;

J. M. Anaya,
None;

B. M. Segal,
None;

N. L. Rhodus,
None;

L. Radfar,
None;

R. H. Scofield,
None;

C. J. Lessard,
None;

K. L. Sivils,
None.

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