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

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.

SUBMITTER: Li H

PROVIDER: S-EPMC5501660 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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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.

Li He H Reksten Tove Ragna TR Ice John A JA Kelly Jennifer A JA Adrianto Indra I Rasmussen Astrid A Wang Shaofeng S He Bo B Grundahl Kiely M KM Glenn Stuart B SB Miceli-Richard Corinne C Bowman Simon S Lester Sue S Eriksson Per P Eloranta Maija-Leena ML Brun Johan G JG Gøransson Lasse G LG Harboe Erna E Guthridge Joel M JM Kaufman Kenneth M KM Kvarnström Marika M Cunninghame Graham Deborah S DS Patel Ketan K Adler Adam J AJ Farris A Darise AD Brennan Michael T MT Chodosh James J Gopalakrishnan Rajaram R Weisman Michael H MH Venuturupalli Swamy S Wallace Daniel J DJ Hefner Kimberly S KS Houston Glen D GD Huang Andrew J W AJW Hughes Pamela J PJ Lewis David M DM Radfar Lida L Vista Evan S ES Edgar Contessa E CE Rohrer Michael D MD Stone Donald U DU Vyse Timothy J TJ Harley John B JB Gaffney Patrick M PM James Judith A JA Turner Sean S Alevizos Ilias I Anaya Juan-Manuel JM Rhodus Nelson L NL Segal Barbara M BM Montgomery Courtney G CG Scofield R Hal RH Kovats Susan S Mariette Xavier X Rönnblom Lars L Witte Torsten T Rischmueller Maureen M Wahren-Herlenius Marie M Omdal Roald R Jonsson Roland R Ng Wan-Fai WF Nordmark Gunnel G Lessard Christopher J CJ Sivils Kathy L KL

PLoS genetics 20170622 6

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 ...[more]

PMID: 28640813

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Project description:BackgroundTrained immunity - or innate immune memory - can be described as the long-term reprogramming of innate immune cells towards a hyperresponsive state which involves intracellular metabolic changes. Trained immunity has been linked to atherosclerosis. A subgroup of patients with primary Sjögren's syndrome (pSS) exhibits systemic type I interferon (IFN) pathway activation, indicating innate immune hyperactivation. Here, we studied the link between type I IFNs and trained immunity in an in vitro monocytic cell model and peripheral blood mononuclear cells (PBMCs) from pSS patients.MethodsThe training stimuli heat killed Candida albicans, muramyl dipeptide, IFNβ, and patient serum were added to THP-1 cells for 24 hours, after which the cells were washed, rested for 48 hours and subsequently re-stimulated with LPS, Pam3Cys, poly I:C, IFNβ or oxLDL for 4-24 hours. PBMCs from pSS patients and healthy controls were stimulated with LPS, Pam3Cys, poly I:C or IFNβ for 0.5-24 hours.ResultsTraining with IFNβ induced elevated production of pro-atherogenic cytokines IL-6, TNFα and CCL2, differential cholesterol- and glycolysis-related gene expression, and increased glucose consumption and oxLDL uptake upon re-stimulation. Type I IFN production was increased in Candida albicans- and IFNβ-trained cells after LPS re-stimulation, but was reduced after poly I:C re-stimulation. Training with muramyl dipeptide and IFNβ, but not Candida albicans, affected the IFN-stimulated gene expression response to IFNβ re-stimulation. PBMCs from pSS patients consumed more glucose compared with healthy control PBMCs and tended to produce more TNFα and type I IFNs upon LPS stimulation, but less type I IFNs upon poly I:C stimulation.ConclusionsType I IFN is a trainer inducing a trained immunity phenotype with pro-atherogenic properties in monocytes. Conversely, trained immunity also affects the production of type I IFNs and transcriptional response to type I IFN receptor re-stimulation. The phenotype of pSS PBMCs is consistent with trained immunity. This connection between type I IFN, trained immunity and cholesterol metabolism may have important implications for pSS and the pathogenesis of (subclinical) atherosclerosis in these patients.

Dataset Information

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

Publications

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

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