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

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. KaufmanMarika 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, for UK Primary Sjögren's Syndrome Registry

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17 Scopus citations

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.

Original languageEnglish (US)
Article numbere1006820
JournalPLoS genetics
Volume13
Issue number6
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We would like to thank the following funding agencies: this publication was made possible by grants from NIH: P50AR0608040 (KLS, CJL, RHS, and ADF), 1R01AR065953 (CJL), 5R01DE015223 (KLS and JBH), 5RC2AR058959 (PMG), 5P01AR049084 (JBH), 5P30AR053483 (JAJ and JMG), 5U19AI082714 (KLS, JAJ, and CJL), U19AI056363 (ADF), 1R01DE018209 (KLS and JBH), 5R01DE018209 (KLS), 8P20GM103456 (PMG, CJL, and IA), 1P30GM110766 (IA and CGM), 1R03AR065786 (IA), 5R37AI024717 (JBH), 5P01AI083194 (KLS and JBH), 7S10RR027190-02 (JBH), 1U01AI101934 (JAJ and JMG), U54GM104938 (JAJ), S10RR026735 (JAJ), and 5P30GM103510 (JAJ and JMG). The contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH. Additional funding was obtained from Intramural Research Program of the National Institute of Dental and Craniofacial Research (GGI), US Department of Veterans Affairs IMMA 9 (JBH), USA Department of Defense PR094002 (JBH), American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award 2009 (CJL and KLS), Oklahoma Medical Research Foundation (CJL and KLS), Sj?gren?s Syndrome Foundation (HL, CJL, and KLS), Phileona Foundation (KLS), French ministry of health: PHRC N?2006-AOM06133 and French ministry of research: ANR-2010-BLAN-1133 (XM and CM), The Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority (LGG, JGB, and RJ), The Broegelmann Foundation (JGB and RJ), Norwegian Foundation for Health and Rehabilitation (EH), KFO 250 TP03, WI 1031/6-1 (TW), KFO 250, Z1 (TW), Medical Research Council, UK G0800629 (WN and SB), Northumberland, Tyne & Wear CLRN (WN), The Swedish Research Council (MW and LR), The King Gustaf the V-th 80-year Foundation (MW and LR), Knut and Alice Wallenberg Foundation (LR), and The Swedish Rheumatism Association (MW, GN, LR, and PE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to all the individuals with Sj?gren?s syndrome and those serving as healthy controls who participated in this study. We would like to thank the following individuals for their help in the collection and ascertainment of the samples used in this study: Erin Rothrock, Judy Harris, Sharon Johnson, Sara Cioli, Nicole Weber, Dominique Williams, Wes Daniels, Cherilyn Pritchett-Frazee, Kylia Crouch, Laura Battiest, Abu N. M. Nazmul-Hossain, Justin Rodgers, James Robertson, Thuan Nguyen, Amanda Crosbie, Ellen James, Carolyn Meyer, Amber McElroy, Eshrat Emamian, Julie Ermer, Kristine Rohlf, Joanlise Leon, Anita Petersen, Danielle Hartle, Jill Novizke, Ward Ortman, Carl Espy, Beth Cobb, Rezvan Kiani, Marianne Eidsheim and Joelle Benessiano Centre de Ressources Biologiques, H?pital Bichat, Paris, France. We would also like to thank Jared Ning for the ongoing assistance in developing and maintaining the computational infrastructure used to perform this study.

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