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Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome
OBJECTIVES: Fatigue is common and severe in primary Sjögren’s syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. METHODS: Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671987/ https://www.ncbi.nlm.nih.gov/pubmed/34907023 http://dx.doi.org/10.1136/rmdopen-2021-001832 |
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author | Norheim, Katrine Brække Imgenberg-Kreuz, Juliana Alexsson, Andrei Johnsen, Svein Joar Auglænd Bårdsen, Kjetil Brun, Johan Gorgas Dehkordi, Rezvan Kiani Theander, Elke Mandl, Thomas Jonsson, Roland Ng, Wan-Fai Lessard, Christopher J Rasmussen, Astrid Sivilis, Kathy Ronnblom, Lars Omdal, Roald |
author_facet | Norheim, Katrine Brække Imgenberg-Kreuz, Juliana Alexsson, Andrei Johnsen, Svein Joar Auglænd Bårdsen, Kjetil Brun, Johan Gorgas Dehkordi, Rezvan Kiani Theander, Elke Mandl, Thomas Jonsson, Roland Ng, Wan-Fai Lessard, Christopher J Rasmussen, Astrid Sivilis, Kathy Ronnblom, Lars Omdal, Roald |
author_sort | Norheim, Katrine Brække |
collection | PubMed |
description | OBJECTIVES: Fatigue is common and severe in primary Sjögren’s syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. METHODS: 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 4 966 157 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. RESULTS: Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10(−8)). Patients homozygous for the major allele scored 25 mm 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. RTP4 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 RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified. CONCLUSION: Genetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS. |
format | Online Article Text |
id | pubmed-8671987 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-86719872021-12-28 Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome Norheim, Katrine Brække Imgenberg-Kreuz, Juliana Alexsson, Andrei Johnsen, Svein Joar Auglænd Bårdsen, Kjetil Brun, Johan Gorgas Dehkordi, Rezvan Kiani Theander, Elke Mandl, Thomas Jonsson, Roland Ng, Wan-Fai Lessard, Christopher J Rasmussen, Astrid Sivilis, Kathy Ronnblom, Lars Omdal, Roald RMD Open Sjögren Syndrome OBJECTIVES: Fatigue is common and severe in primary Sjögren’s syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. METHODS: 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 4 966 157 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. RESULTS: Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10(−8)). Patients homozygous for the major allele scored 25 mm 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. RTP4 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 RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified. CONCLUSION: Genetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS. BMJ Publishing Group 2021-12-14 /pmc/articles/PMC8671987/ /pubmed/34907023 http://dx.doi.org/10.1136/rmdopen-2021-001832 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Sjögren Syndrome Norheim, Katrine Brække Imgenberg-Kreuz, Juliana Alexsson, Andrei Johnsen, Svein Joar Auglænd Bårdsen, Kjetil Brun, Johan Gorgas Dehkordi, Rezvan Kiani Theander, Elke Mandl, Thomas Jonsson, Roland Ng, Wan-Fai Lessard, Christopher J Rasmussen, Astrid Sivilis, Kathy Ronnblom, Lars Omdal, Roald Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome |
title | Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome |
title_full | Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome |
title_fullStr | Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome |
title_full_unstemmed | Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome |
title_short | Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren’s syndrome |
title_sort | genetic variants at the rtp4/masp1 locus are associated with fatigue in scandinavian patients with primary sjögren’s syndrome |
topic | Sjögren Syndrome |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671987/ https://www.ncbi.nlm.nih.gov/pubmed/34907023 http://dx.doi.org/10.1136/rmdopen-2021-001832 |
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