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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 LU ; Mandl, Thomas LU and Jonsson, Roland , et al. (2021) In RMD Open 7(3). p.1-9
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
RMD Open
volume
7
issue
3
article number
e001832
pages
1 - 9
publisher
BMJ Publishing Group
external identifiers
  • pmid:34907023
  • scopus:85122153815
ISSN
2056-5933
DOI
10.1136/rmdopen-2021-001832
language
English
LU publication?
yes
additional info
© 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.
id
f9ef7570-7283-44ac-bc2a-c4afde3b6940
date added to LUP
2021-12-16 10:11:44
date last changed
2022-09-17 20:17:45
@article{f9ef7570-7283-44ac-bc2a-c4afde3b6940,
  abstract     = {{<p>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.</p><p>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.</p><p>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&lt;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.</p><p>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.</p>}},
  author       = {{Norheim, Katrine Brække and Imgenberg-Kreuz, Juliana and Alexsson, Andrei and Johnsen, Svein Joar Auglænd and Bårdsen, Kjetil and Brun, Johan Gorgas and Dehkordi, Rezvan Kiani and Theander, Elke and Mandl, Thomas and Jonsson, Roland and Ng, Wan-Fai and Lessard, Christopher J and Rasmussen, Astrid and Sivilis, Kathy and Ronnblom, Lars and Omdal, Roald}},
  issn         = {{2056-5933}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{1--9}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{RMD Open}},
  title        = {{Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren's syndrome}},
  url          = {{http://dx.doi.org/10.1136/rmdopen-2021-001832}},
  doi          = {{10.1136/rmdopen-2021-001832}},
  volume       = {{7}},
  year         = {{2021}},
}