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 Kaufman & 31 otros 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,

Resultado de la investigación: Contribución a RevistaArtículo

9 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)e1006820
PublicaciónPLoS Genetics
Volumen13
N.º6
DOI
EstadoPublished - jun 22 2017
Publicado de forma externa

Huella dactilar

Interferon Type I
Sjogren's Syndrome
interferons
Ligases
ligases
Protein Isoforms
protein synthesis
loci
protein
allele
Interferons
disease severity
autoantibodies
meta-analysis
fatigue
Autoantibodies
confidence interval
genotype
Alleles
Keratoconjunctivitis Sicca

Citar esto

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. / Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. En: PLoS Genetics. 2017 ; Vol. 13, N.º 6. pp. e1006820.
@article{04401d92013049d2a25ba2dea495ed05,
title = "Identification of a Sj{\"o}gren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons",
abstract = "Sj{\"o}gren'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.",
author = "He Li and Reksten, {Tove Ragna} and Ice, {John A} and Kelly, {Jennifer A} and Indra Adrianto and Astrid Rasmussen and Shaofeng Wang and Bo He and Grundahl, {Kiely M} and Glenn, {Stuart B} and Corinne Miceli-Richard and Simon Bowman and Sue Lester and Per Eriksson and Maija-Leena Eloranta and Brun, {Johan G} and G{\o}ransson, {Lasse G} and Erna Harboe and Guthridge, {Joel M} and Kaufman, {Kenneth M} and Marika Kvarnstr{\"o}m and {Cunninghame Graham}, {Deborah S} and Ketan Patel and Adler, {Adam J} and Farris, {A Darise} and Brennan, {Michael T} and James Chodosh and Rajaram Gopalakrishnan and Weisman, {Michael H} and Swamy Venuturupalli and Wallace, {Daniel J} and Hefner, {Kimberly S} and Houston, {Glen D} and Huang, {Andrew J W} and Hughes, {Pamela J} and Lewis, {David M} and Lida Radfar and Vista, {Evan S} and Edgar, {Contessa E} and Rohrer, {Michael D} and Stone, {Donald U} and Vyse, {Timothy J} and Harley, {John B} and Gaffney, {Patrick M} and James, {Judith A} and Sean Turner and Ilias Alevizos and Juan-Manuel Anaya and Rhodus, {Nelson L} and Segal, {Barbara M}",
year = "2017",
month = "6",
day = "22",
doi = "10.1371/journal.pgen.1006820",
language = "English (US)",
volume = "13",
pages = "e1006820",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "6",

}

Li, H, Reksten, TR, Ice, JA, Kelly, JA, Adrianto, I, Rasmussen, A, Wang, S, He, B, Grundahl, KM, Glenn, SB, Miceli-Richard, C, Bowman, S, Lester, S, Eriksson, P, Eloranta, M-L, Brun, JG, Gøransson, LG, Harboe, E, Guthridge, JM, Kaufman, KM, Kvarnström, M, Cunninghame Graham, DS, Patel, K, Adler, AJ, Farris, AD, Brennan, MT, Chodosh, J, Gopalakrishnan, R, Weisman, MH, Venuturupalli, S, Wallace, DJ, Hefner, KS, Houston, GD, Huang, AJW, Hughes, PJ, Lewis, DM, Radfar, L, Vista, ES, Edgar, CE, Rohrer, MD, Stone, DU, Vyse, TJ, Harley, JB, Gaffney, PM, James, JA, Turner, S, Alevizos, I, Anaya, J-M, Rhodus, NL, Segal, BM 2017, 'Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons', PLoS Genetics, vol. 13, n.º 6, pp. e1006820. https://doi.org/10.1371/journal.pgen.1006820

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.

En: PLoS Genetics, Vol. 13, N.º 6, 22.06.2017, p. e1006820.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons

AU - Li, He

AU - Reksten, Tove Ragna

AU - Ice, John A

AU - Kelly, Jennifer A

AU - Adrianto, Indra

AU - Rasmussen, Astrid

AU - Wang, Shaofeng

AU - He, Bo

AU - Grundahl, Kiely M

AU - Glenn, Stuart B

AU - Miceli-Richard, Corinne

AU - Bowman, Simon

AU - Lester, Sue

AU - Eriksson, Per

AU - Eloranta, Maija-Leena

AU - Brun, Johan G

AU - Gøransson, Lasse G

AU - Harboe, Erna

AU - Guthridge, Joel M

AU - Kaufman, Kenneth M

AU - Kvarnström, Marika

AU - Cunninghame Graham, Deborah S

AU - Patel, Ketan

AU - Adler, Adam J

AU - Farris, A Darise

AU - Brennan, Michael T

AU - Chodosh, James

AU - Gopalakrishnan, Rajaram

AU - Weisman, Michael H

AU - Venuturupalli, Swamy

AU - Wallace, Daniel J

AU - Hefner, Kimberly S

AU - Houston, Glen D

AU - Huang, Andrew J W

AU - Hughes, Pamela J

AU - Lewis, David M

AU - Radfar, Lida

AU - Vista, Evan S

AU - Edgar, Contessa E

AU - Rohrer, Michael D

AU - Stone, Donald U

AU - Vyse, Timothy J

AU - Harley, John B

AU - Gaffney, Patrick M

AU - James, Judith A

AU - Turner, Sean

AU - Alevizos, Ilias

AU - Anaya, Juan-Manuel

AU - Rhodus, Nelson L

AU - Segal, Barbara M

PY - 2017/6/22

Y1 - 2017/6/22

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1006820

DO - 10.1371/journal.pgen.1006820

M3 - Article

VL - 13

SP - e1006820

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 6

ER -