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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Li, HeOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA.;Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA.,Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA (författare)

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

Artikel/kapitelEngelska2017

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2017-06-22
PUBLIC LIBRARY SCIENCE,2017
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-330755
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330755URI
https://doi.org/10.1371/journal.pgen.1006820DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:136143637URI
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-139633URI

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Språk:engelska
Sammanfattning på:engelska

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Funding Agencies|NIH [P50AR0608040, 1R01AR065953, 5R01DE015223, 5RC2AR058959, 5P01AR049084, 5P30AR053483, 5U19AI082714, U19AI056363, 1R01DE018209, 5R01DE018209, 8P20GM103456, 1P30GM110766, 1R03AR065786, 5R37AI024717, 5P01AI083194, 7S10RR027190-02, 1U01AI101934, U54GM104938, S10RR026735, 5P30GM103510]; National Institute of Dental and Craniofacial Research; US Department of Veterans Affairs IM MA 9; USA Department of Defense [PR094002]; American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award; Oklahoma Medical Research Foundation; Sjogrens Syndrome Foundation; Phileona Foundation; French ministry of health: PHRC [2006-AOM06133]; French ministry of research [ANR-2010-BLAN-1133]
Sjogren'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 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 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.

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Biuppslag (personer, institutioner, konferenser, titlar ...)

Reksten, Tove RagnaOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway.,Oklahoma Medical Research Fdn, OK 73104 USA; University of Bergen, Norway (författare)
Ice, John A.Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.,Oklahoma Medical Research Fdn, OK 73104 USA (författare)
Kelly, Jennifer A.Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.,Oklahoma Medical Research Fdn, OK 73104 USA (författare)
Adrianto, IndraOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.,Oklahoma Medical Research Fdn, OK 73104 USA (författare)
Rasmussen, AstridOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.,Oklahoma Medical Research Fdn, OK 73104 USA (författare)
Wang, ShaofengOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.,Oklahoma Medical Research Fdn, OK 73104 USA (författare)
He, BoOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA.,Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA (författare)
Grundahl, Kiely M.Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.,Oklahoma Medical Research Fdn, OK 73104 USA (författare)
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Eloranta, Maija-LeenaUppsala universitet,Reumatologi,Science for Life Laboratory, SciLifeLab,Uppsala University, Sweden(Swepub:uu)maelo020 (författare)
Brun, Johan G.Univ Bergen, Dept Clin Sci, Bergen, Norway.;Haukeland Hosp, Dept Rheumatol, Bergen, Norway.,University of Bergen, Norway; Haukeland Hospital, Norway (författare)
Goransson, Lasse G.Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway.,Stavanger University Hospital, Norway (författare)
Harboe, ErnaStavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway.,Stavanger University Hospital, Norway (författare)
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Kvarnstrom, MarikaKarolinska Institutet,Karolinska Inst, Dept Med, Stockholm, Sweden.,Karolinska Institute, Sweden (författare)
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Patel, KetanUniv Minnesota, Sch Dent, Dept Dev & Surg Sci, Div Oral & Maxillofacial Surg, Minneapolis, MN 55455 USA.;North Mem Med Ctr, Dept Oral & Maxillofacial Surg, Robbinsdale, MN USA.,University of Minnesota, MN 55455 USA; North Mem Medical Centre, MN USA (författare)
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Farris, A. DariseOklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA.,Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA (författare)
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Hughes, Pamela J.Univ Minnesota, Sch Dent, Dept Dev & Surg Sci, Div Oral & Maxillofacial Surg, Minneapolis, MN 55455 USA.,University of Minnesota, MN 55455 USA (författare)
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Rischmueller, MaureenQueen Elizabeth Hosp, Adelaide, SA, Australia.;Univ Adelaide, Adelaide, SA, Australia.,Queen Elizabeth Hospital, Australia; University of Adelaide, Australia (författare)
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Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA.;Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA.Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA (creator_code:org_t)

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