{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:23:41Z","timestamp":1787495021564,"version":"build-2736575974"},"reference-count":50,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"unspecified","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G0800629"],"award-info":[{"award-number":["G0800629"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"King Gustav the V:th 80-year foundation"},{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","award":["911783"],"award-info":[{"award-number":["911783"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","award":["911807"],"award-info":[{"award-number":["911807"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","award":["912043"],"award-info":[{"award-number":["912043"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Philonea Foundation"},{"DOI":"10.13039\/501100008166","name":"British Sj\u00f6gren's Syndrome Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Erik, Karin and Gosta Selanders Foundation"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50AR0608040"],"award-info":[{"award-number":["P50AR0608040"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR065953"],"award-info":[{"award-number":["R01AR065953"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR50782"],"award-info":[{"award-number":["R01AR50782"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DE018209"],"award-info":[{"award-number":["R01DE018209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01DE017593"],"award-info":[{"award-number":["U01DE017593"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19AI082714"],"award-info":[{"award-number":["U19AI082714"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007949","name":"Reumatikerf\u00f6rbundet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008907","name":"Oklahoma Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008907","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007051","name":"Uppsala Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006636","name":"Forskningsr\u00e5det om H\u00e4lsa, Arbetsliv och V\u00e4lf\u00e4rd","doi-asserted-by":"publisher","award":["2016-01982"],"award-info":[{"award-number":["2016-01982"]}],"id":[{"id":"10.13039\/501100006636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006636","name":"Forskningsr\u00e5det om H\u00e4lsa, Arbetsliv och V\u00e4lf\u00e4rd","doi-asserted-by":"publisher","award":["2018-02399"],"award-info":[{"award-number":["2018-02399"]}],"id":[{"id":"10.13039\/501100006636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007687","name":"Svenska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007687","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2021,11,19]]},"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Fatigue is common and severe in primary Sj\u00f6gren\u2019s syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4\u2009966\u2009157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (\n                      <jats:italic>RTP4)\/MASP1<\/jats:italic>\n                      locus associated with fatigue with genome-wide significance (GWS) (p&lt;5\u00d710\n                      <jats:sup>\u22128<\/jats:sup>\n                      ). Patients homozygous for the major allele scored 25\u2009mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US\/UK cohorts, or all four cohorts.\n                      <jats:italic>RTP4<\/jats:italic>\n                      expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at\n                      <jats:italic>RTP4\/MASP1<\/jats:italic>\n                      and levels of\n                      <jats:italic>RTP4<\/jats:italic>\n                      and\n                      <jats:italic>MASP1<\/jats:italic>\n                      expression were identified.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Genetic variations at\n                      <jats:italic>RTP4\/MASP1<\/jats:italic>\n                      are associated with fatigue in Scandinavian pSS patients.\n                      <jats:italic>RTP4<\/jats:italic>\n                      encodes a Golgi chaperone that influences opioid pain receptor function and\n                      <jats:italic>MASP1<\/jats:italic>\n                      is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2021-001832","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T11:30:13Z","timestamp":1639481413000},"page":"e001832","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Genetic variants at the\n                    <i>RTP4\/MASP1<\/i>\n                    locus are associated with fatigue in Scandinavian patients with primary Sj\u00f6gren\u2019s syndrome"],"prefix":"10.1136","volume":"7","author":[{"given":"Katrine Br\u00e6kke","family":"Norheim","sequence":"first","affiliation":[{"name":"Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway"},{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Imgenberg-Kreuz","sequence":"additional","affiliation":[{"name":"Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway"},{"name":"Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Alexsson","sequence":"additional","affiliation":[{"name":"Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svein Joar Augl\u00e6nd","family":"Johnsen","sequence":"additional","affiliation":[{"name":"Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjetil","family":"B\u00e5rdsen","sequence":"additional","affiliation":[{"name":"Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan Gorgas","family":"Brun","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"},{"name":"Department of Rheumatology, Haukeland University Hospital, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rezvan Kiani","family":"Dehkordi","sequence":"additional","affiliation":[{"name":"Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Theander","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Lund University, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Mandl","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Lund University, Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Jonsson","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Fai","family":"Ng","sequence":"additional","affiliation":[{"name":"Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK"},{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Lessard","sequence":"additional","affiliation":[{"name":"Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Sivilis","sequence":"additional","affiliation":[{"name":"Translational Sciences, Rheumatology, Janssen Pharmaceutical Companies of Johnson and Johnson, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Ronnblom","sequence":"additional","affiliation":[{"name":"Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6051-4658","authenticated-orcid":false,"given":"Roald","family":"Omdal","sequence":"additional","affiliation":[{"name":"Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway"},{"name":"Department of Clinical Science, University of Bergen, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"2025090312551667000_7.3.e001832.1","doi-asserted-by":"publisher","DOI":"10.1097\/00019052-199612000-00011"},{"key":"2025090312551667000_7.3.e001832.2","first-page":"255","article-title":"Physical fatigue characterises patient experience of primary Sj\u00f6gren's syndrome","volume":"35","author":"Arends","year":"2017","journal-title":"Clin Exp Rheumatol"},{"key":"2025090312551667000_7.3.e001832.3","doi-asserted-by":"publisher","DOI":"10.1186\/ar3487"},{"key":"2025090312551667000_7.3.e001832.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2013.10.003"},{"key":"2025090312551667000_7.3.e001832.5","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1097\/WCO.0000000000000817","article-title":"The biological basis of chronic fatigue: neuroinflammation and innate immunity","volume":"33","author":"Omdal","year":"2020","journal-title":"Curr Opin Neurol"},{"key":"2025090312551667000_7.3.e001832.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-7634(88)80004-6"},{"key":"2025090312551667000_7.3.e001832.7","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/acr.22263","article-title":"Primary Sj\u00f6gren's syndrome: fatigue is an ever-present, fluctuating, and uncontrollable lack of energy","volume":"66","author":"Mengshoel","year":"2014","journal-title":"Arthritis Care Res"},{"key":"2025090312551667000_7.3.e001832.8","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.bbi.2017.01.007","article-title":"A systematic review of the association between fatigue and genetic polymorphisms","volume":"62","author":"Wang","year":"2017","journal-title":"Brain Behav Immun"},{"key":"2025090312551667000_7.3.e001832.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pmrj.2010.04.003"},{"key":"2025090312551667000_7.3.e001832.10","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew008"},{"key":"2025090312551667000_7.3.e001832.11","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2792"},{"key":"2025090312551667000_7.3.e001832.12","doi-asserted-by":"publisher","DOI":"10.1136\/ard.61.6.554"},{"key":"2025090312551667000_7.3.e001832.13","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.110619"},{"key":"2025090312551667000_7.3.e001832.14","first-page":"1896","article-title":"Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients","volume":"31","author":"Wolfe","year":"2004","journal-title":"J Rheumatol"},{"key":"2025090312551667000_7.3.e001832.15","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204615"},{"key":"2025090312551667000_7.3.e001832.16","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"2025090312551667000_7.3.e001832.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"2025090312551667000_7.3.e001832.18","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1596"},{"key":"2025090312551667000_7.3.e001832.19","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2924"},{"key":"2025090312551667000_7.3.e001832.20","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208659"},{"key":"2025090312551667000_7.3.e001832.21","doi-asserted-by":"crossref","DOI":"10.1111\/sji.12662","article-title":"Transcription profiling of peripheral B cells in antibody-positive primary Sj\u00f6gren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature","volume":"87","author":"Imgenberg-Kreuz","year":"2018","journal-title":"Scand J Immunol"},{"key":"2025090312551667000_7.3.e001832.22","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2756"},{"key":"2025090312551667000_7.3.e001832.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0804106105"},{"key":"2025090312551667000_7.3.e001832.24","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2018.2"},{"key":"2025090312551667000_7.3.e001832.25","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq454"},{"key":"2025090312551667000_7.3.e001832.26","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0083149","article-title":"Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons","volume":"8","author":"Hoyo-Becerra","year":"2013","journal-title":"PLoS One"},{"key":"2025090312551667000_7.3.e001832.27","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0038668","article-title":"Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy","volume":"7","author":"Schlaak","year":"2012","journal-title":"PLoS One"},{"key":"2025090312551667000_7.3.e001832.28","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-014-8861-z"},{"key":"2025090312551667000_7.3.e001832.29","first-page":"21","article-title":"The importance of the type I interferon system in autoimmunity","volume":"34","author":"R\u00f6nnblom","year":"2016","journal-title":"Clin Exp Rheumatol"},{"key":"2025090312551667000_7.3.e001832.30","article-title":"Innate immunity and interferons in the pathogenesis of Sj\u00f6gren's syndrome","author":"Bodewes","year":"2019","journal-title":"Rheumatology"},{"key":"2025090312551667000_7.3.e001832.31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.9.6132"},{"key":"2025090312551667000_7.3.e001832.32","doi-asserted-by":"crossref","first-page":"205031211985039","DOI":"10.1177\/2050312119850390","article-title":"Fatigue in primary Sj\u00f6gren's syndrome: a proteomic pilot study of cerebrospinal fluid","volume":"7","author":"Larssen","year":"2019","journal-title":"SAGE Open Med"},{"key":"2025090312551667000_7.3.e001832.33","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.24.8506-8513.2002"},{"key":"2025090312551667000_7.3.e001832.34","doi-asserted-by":"publisher","DOI":"10.1177\/1753425916633236"},{"key":"2025090312551667000_7.3.e001832.35","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-139"},{"key":"2025090312551667000_7.3.e001832.36","doi-asserted-by":"publisher","DOI":"10.1038\/ng.717"},{"key":"2025090312551667000_7.3.e001832.37","doi-asserted-by":"publisher","DOI":"10.1038\/ng.468"},{"key":"2025090312551667000_7.3.e001832.38","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-004-0463-z"},{"key":"2025090312551667000_7.3.e001832.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2009.06.151"},{"key":"2025090312551667000_7.3.e001832.40","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1196"},{"key":"2025090312551667000_7.3.e001832.41","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-015-0226-6"},{"key":"2025090312551667000_7.3.e001832.42","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0030123","article-title":"Interleukin-1 Inhibition and Fatigue in Primary Sj\u00f6gren\u2019s Syndrome \u2013 A Double Blind, Randomised Clinical Trial","volume":"7","author":"Norheim","year":"2017","journal-title":"PLoS One"},{"key":"2025090312551667000_7.3.e001832.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2011.04.001"},{"key":"2025090312551667000_7.3.e001832.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2011.12.007"},{"key":"2025090312551667000_7.3.e001832.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2014.10.008"},{"key":"2025090312551667000_7.3.e001832.46","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1186\/s13075-015-0784-1","article-title":"Fatigue in chronic inflammation - a link to pain pathways","volume":"17","author":"Louati","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"2025090312551667000_7.3.e001832.47","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.01696","article-title":"The role of inflammation in depression and fatigue","volume":"10","author":"Lee","year":"2019","journal-title":"Front Immunol"},{"key":"2025090312551667000_7.3.e001832.48","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keq043"},{"key":"2025090312551667000_7.3.e001832.49","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/bjd.15375","article-title":"Fatigue in psoriasis: a controlled study","volume":"177","author":"Skoie","year":"2017","journal-title":"Br J Dermatol"},{"key":"2025090312551667000_7.3.e001832.50","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjv091"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2021-001832","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T19:55:24Z","timestamp":1756929324000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2021-001832"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,12,14]]},"published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1136\/rmdopen-2021-001832"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2021-001832","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12]]}}}