Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.
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 interf...
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2017-06-01
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| Series: | PLoS Genetics |
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| author | He Li Tove Ragna Reksten John A Ice Jennifer A Kelly Indra Adrianto Astrid Rasmussen Shaofeng Wang Bo He Kiely M Grundahl Stuart B Glenn Corinne Miceli-Richard Simon Bowman Sue Lester Per Eriksson Maija-Leena Eloranta Johan G Brun Lasse G Gøransson Erna Harboe Joel M Guthridge Kenneth M Kaufman Marika Kvarnström Deborah S Cunninghame Graham Ketan Patel Adam J Adler A Darise Farris Michael T Brennan James Chodosh Rajaram Gopalakrishnan Michael H Weisman Swamy Venuturupalli Daniel J Wallace Kimberly S Hefner Glen D Houston Andrew J W Huang Pamela J Hughes David M Lewis Lida Radfar Evan S Vista Contessa E Edgar Michael D Rohrer Donald U Stone Timothy J Vyse John B Harley Patrick M Gaffney Judith A James Sean Turner Ilias Alevizos Juan-Manuel Anaya Nelson L Rhodus Barbara M Segal Courtney G Montgomery R Hal Scofield Susan Kovats Xavier Mariette Lars Rönnblom Torsten Witte Maureen Rischmueller Marie Wahren-Herlenius Roald Omdal Roland Jonsson Wan-Fai Ng for UK Primary Sjögren's Syndrome Registry Gunnel Nordmark Christopher J Lessard Kathy L Sivils |
| author_facet | He Li Tove Ragna Reksten John A Ice Jennifer A Kelly Indra Adrianto Astrid Rasmussen Shaofeng Wang Bo He Kiely M Grundahl Stuart B Glenn Corinne Miceli-Richard Simon Bowman Sue Lester Per Eriksson Maija-Leena Eloranta Johan G Brun Lasse G Gøransson Erna Harboe Joel M Guthridge Kenneth M Kaufman Marika Kvarnström Deborah S Cunninghame Graham Ketan Patel Adam J Adler A Darise Farris Michael T Brennan James Chodosh Rajaram Gopalakrishnan Michael H Weisman Swamy Venuturupalli Daniel J Wallace Kimberly S Hefner Glen D Houston Andrew J W Huang Pamela J Hughes David M Lewis Lida Radfar Evan S Vista Contessa E Edgar Michael D Rohrer Donald U Stone Timothy J Vyse John B Harley Patrick M Gaffney Judith A James Sean Turner Ilias Alevizos Juan-Manuel Anaya Nelson L Rhodus Barbara M Segal Courtney G Montgomery R Hal Scofield Susan Kovats Xavier Mariette Lars Rönnblom Torsten Witte Maureen Rischmueller Marie Wahren-Herlenius Roald Omdal Roland Jonsson Wan-Fai Ng for UK Primary Sjögren's Syndrome Registry Gunnel Nordmark Christopher J Lessard Kathy L Sivils |
| author_sort | He Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-de75960e36dc428c8be5c64c20d692ba |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2017-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-de75960e36dc428c8be5c64c20d692ba2025-08-20T03:19:53ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-06-01136e100682010.1371/journal.pgen.1006820Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.He LiTove Ragna RekstenJohn A IceJennifer A KellyIndra AdriantoAstrid RasmussenShaofeng WangBo HeKiely M GrundahlStuart B GlennCorinne Miceli-RichardSimon BowmanSue LesterPer ErikssonMaija-Leena ElorantaJohan G BrunLasse G GøranssonErna HarboeJoel M GuthridgeKenneth M KaufmanMarika KvarnströmDeborah S Cunninghame GrahamKetan PatelAdam J AdlerA Darise FarrisMichael T BrennanJames ChodoshRajaram GopalakrishnanMichael H WeismanSwamy VenuturupalliDaniel J WallaceKimberly S HefnerGlen D HoustonAndrew J W HuangPamela J HughesDavid M LewisLida RadfarEvan S VistaContessa E EdgarMichael D RohrerDonald U StoneTimothy J VyseJohn B HarleyPatrick M GaffneyJudith A JamesSean TurnerIlias AlevizosJuan-Manuel AnayaNelson L RhodusBarbara M SegalCourtney G MontgomeryR Hal ScofieldSusan KovatsXavier MarietteLars RönnblomTorsten WitteMaureen RischmuellerMarie Wahren-HerleniusRoald OmdalRoland JonssonWan-Fai Ngfor UK Primary Sjögren's Syndrome RegistryGunnel NordmarkChristopher J LessardKathy L SivilsSjögren'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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006820&type=printable |
| spellingShingle | He Li Tove Ragna Reksten John A Ice Jennifer A Kelly Indra Adrianto Astrid Rasmussen Shaofeng Wang Bo He Kiely M Grundahl Stuart B Glenn Corinne Miceli-Richard Simon Bowman Sue Lester Per Eriksson Maija-Leena Eloranta Johan G Brun Lasse G Gøransson Erna Harboe Joel M Guthridge Kenneth M Kaufman Marika Kvarnström Deborah S Cunninghame Graham Ketan Patel Adam J Adler A Darise Farris Michael T Brennan James Chodosh Rajaram Gopalakrishnan Michael H Weisman Swamy Venuturupalli Daniel J Wallace Kimberly S Hefner Glen D Houston Andrew J W Huang Pamela J Hughes David M Lewis Lida Radfar Evan S Vista Contessa E Edgar Michael D Rohrer Donald U Stone Timothy J Vyse John B Harley Patrick M Gaffney Judith A James Sean Turner Ilias Alevizos Juan-Manuel Anaya Nelson L Rhodus Barbara M Segal Courtney G Montgomery R Hal Scofield Susan Kovats Xavier Mariette Lars Rönnblom Torsten Witte Maureen Rischmueller Marie Wahren-Herlenius Roald Omdal Roland Jonsson Wan-Fai Ng for UK Primary Sjögren's Syndrome Registry Gunnel Nordmark Christopher J Lessard Kathy L Sivils Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genetics |
| title | Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. |
| title_full | Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. |
| title_fullStr | Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. |
| title_full_unstemmed | Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. |
| title_short | Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. |
| title_sort | identification of a sjogren s syndrome susceptibility locus at oas1 that influences isoform switching protein expression and responsiveness to type i interferons |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006820&type=printable |
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