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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 ; Reksten, Tove Ragna ; Ice, John A ; Kelly, Jennifer A ; Adrianto, Indra ; Rasmussen, Astrid ; Wang, Shaofeng ; He, Bo ; Grundahl, Kiely M ; Glenn, Stuart B ; Miceli-Richard, Corinne ; Bowman, Simon ; Lester, Sue ; Eriksson, Per ; Eloranta, Maija-Leena ; Brun, Johan G ; Gøransson, Lasse G ; Harboe, Erna ; Guthridge, Joel M ; Kaufman, Kenneth M ; Kvarnström, Marika ; Cunninghame Graham, Deborah S ; Patel, Ketan ; Adler, Adam J ; Farris, A Darise ; Brennan, Michael T ; Chodosh, James ; Gopalakrishnan, Rajaram ; Weisman, Michael H ; Venuturupalli, Swamy ; Wallace, Daniel J ; Hefner, Kimberly S ; Houston, Glen D ; Huang, Andrew J W ; Hughes, Pamela J ; Lewis, David M ; Radfar, Lida ; Vista, Evan S ; Edgar, Contessa E ; Rohrer, Michael D ; Stone, Donald U ; Vyse, Timothy J ; Harley, John B ; Gaffney, Patrick M ; James, Judith A ; Turner, Sean ; Alevizos, Ilias ; Anaya, Juan-Manuel ; Rhodus, Nelson L ; Segal, Barbara M ; Montgomery, Courtney G ; Scofield, R Hal ; Kovats, Susan ; Mariette, Xavier ; Rönnblom, Lars ; Witte, Torsten ; Rischmueller, Maureen ; Wahren-Herlenius, Marie ; Omdal, Roald ; Jonsson, Roland ; Ng, Wan-Fai ; Nordmark, Gunnel ; Lessard, Christopher J ; Sivils, Kathy L Trynka, Gosia

PLoS genetics, 2017-06, Vol.13 (6), p.e1006820-e1006820 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
Autor: Li, He ; Reksten, Tove Ragna ; Ice, John A ; Kelly, Jennifer A ; Adrianto, Indra ; Rasmussen, Astrid ; Wang, Shaofeng ; He, Bo ; Grundahl, Kiely M ; Glenn, Stuart B ; Miceli-Richard, Corinne ; Bowman, Simon ; Lester, Sue ; Eriksson, Per ; Eloranta, Maija-Leena ; Brun, Johan G ; Gøransson, Lasse G ; Harboe, Erna ; Guthridge, Joel M ; Kaufman, Kenneth M ; Kvarnström, Marika ; Cunninghame Graham, Deborah S ; Patel, Ketan ; Adler, Adam J ; Farris, A Darise ; Brennan, Michael T ; Chodosh, James ; Gopalakrishnan, Rajaram ; Weisman, Michael H ; Venuturupalli, Swamy ; Wallace, Daniel J ; Hefner, Kimberly S ; Houston, Glen D ; Huang, Andrew J W ; Hughes, Pamela J ; Lewis, David M ; Radfar, Lida ; Vista, Evan S ; Edgar, Contessa E ; Rohrer, Michael D ; Stone, Donald U ; Vyse, Timothy J ; Harley, John B ; Gaffney, Patrick M ; James, Judith A ; Turner, Sean ; Alevizos, Ilias ; Anaya, Juan-Manuel ; Rhodus, Nelson L ; Segal, Barbara M ; Montgomery, Courtney G ; Scofield, R Hal ; Kovats, Susan ; Mariette, Xavier ; Rönnblom, Lars ; Witte, Torsten ; Rischmueller, Maureen ; Wahren-Herlenius, Marie ; Omdal, Roald ; Jonsson, Roland ; Ng, Wan-Fai ; Nordmark, Gunnel ; Lessard, Christopher J ; Sivils, Kathy L
Trynka, Gosia
Assuntos: 2',5'-Oligoadenylate Synthetase - biosynthesis ; 2',5'-Oligoadenylate Synthetase - genetics ; Alleles ; Alternative splicing ; Alternative Splicing - genetics ; Arthritis ; Autoantibodies ; Bioinformatics ; Biology and Life Sciences ; Dentistry ; Enzymatic activity ; Fatigue ; Female ; Gene expression ; Gene Expression Regulation ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genomes ; Genomics ; Haplotypes ; Health sciences ; Hospitals ; Humans ; Immunology ; Interferon ; Interferon Type I - genetics ; Interferon Type I - metabolism ; Internal medicine ; Isoforms ; Keratoconjunctivitis ; Laboratories ; Lymphoma ; Male ; Maxillofacial surgery ; Medical research ; Medicin och hälsovetenskap ; Medicine ; Medicine and Health Sciences ; Neuropathy ; Pathology ; Physicians ; Principal components analysis ; Quantitative trait loci ; Quantitative Trait Loci - genetics ; Research and Analysis Methods ; Rheumatology ; Risk ; Sjogren's syndrome ; Sjogren's Syndrome - genetics ; Sjogren's Syndrome - metabolism ; Sjogren's Syndrome - pathology ; Splicing ; Stimulation ; Surgery ; Susceptibility ; Transcription ; Vasculitis ; Virus Diseases - genetics ; Virus Diseases - virology ; Visualization ; Xerostomia
É parte de: PLoS genetics, 2017-06, Vol.13 (6), p.e1006820-e1006820
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These are joint senior authors on this work.
Conceived and designed the experiments: HL CJL KLS.Performed the experiments: HL SW BH KMK AJA ST.Analyzed the data: HL JAI JAK IAd CGM CJL KLS.Contributed reagents/materials/analysis tools: HL JAI JAK AR KMG SBG CMR SB SL PE MLE JGB LGG EH JMG MK DSCG KP ADF MTB JC RG MHW SV DJW KSH GDH AJWH PJH DML LRa ESV CEE MDR DUS TJV JBH PMG JAJ IAl JMA NLR BMS CGM RHS SK XM LRö TW MR MWH RO RJ WFN GN CJL KLS.Wrote the paper: HL TRR CJL KLS.
Current address: Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, United States of America
Membership of UK Primary Sjögren's Syndrome Registry is provided in S1 Text
The authors have declared that no competing interests exist.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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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

United States: Public Library of Science

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