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Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

Authors :
Li H
Reksten TR
Ice JA
Kelly JA
Adrianto I
Rasmussen A
Wang S
He B
Grundahl KM
Glenn SB
Miceli-Richard C
Bowman S
Lester S
Eriksson P
Eloranta ML
Brun JG
Gøransson LG
Harboe E
Guthridge JM
Kaufman KM
Kvarnström M
Cunninghame Graham DS
Patel K
Adler AJ
Farris AD
Brennan MT
Chodosh J
Gopalakrishnan R
Weisman MH
Venuturupalli S
Wallace DJ
Hefner KS
Houston GD
Huang AJW
Hughes PJ
Lewis DM
Radfar L
Vista ES
Edgar CE
Rohrer MD
Stone DU
Vyse TJ
Harley JB
Gaffney PM
James JA
Turner S
Alevizos I
Anaya JM
Rhodus NL
Segal BM
Montgomery CG
Scofield RH
Kovats S
Mariette X
Rönnblom L
Witte T
Rischmueller M
Wahren-Herlenius M
Omdal R
Jonsson R
Ng WF
Nordmark G
Lessard CJ
Sivils KL
Source :
PLoS genetics [PLoS Genet] 2017 Jun 22; Vol. 13 (6), pp. e1006820. Date of Electronic Publication: 2017 Jun 22 (Print Publication: 2017).
Publication Year :
2017

Abstract

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

Details

Language :
English
ISSN :
1553-7404
Volume :
13
Issue :
6
Database :
MEDLINE
Journal :
PLoS genetics
Publication Type :
Academic Journal
Accession number :
28640813
Full Text :
https://doi.org/10.1371/journal.pgen.1006820