Genetic Determinants of Fatigue in Primary Sjögren`s Syndrome – a Genome Wide Association Study

Katrine Norheim¹, Andrei Alexsson², Juliana Imgenberg-Kreuz³, Johan Gorgas Brun^4,5, Roland Jonsson⁶, Wan-Fai Ng^7,8, Elke Theander⁹, Thomas Mandl¹⁰, Kathy L. Sivils¹¹, Lars Rönnblom¹², Gunnel Nordmark¹³ and Roald Omdal^5,14, ¹Clinical Immunology Department, Stavanger University Hospital, Stavanger, Norway, ²Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden, Uppsala, Sweden, ³Department of Medical Sciences, Uppsala University, Uppsala, Sweden, ⁴Section for Rheumatology, Haukeland University Hospital, Bergen, Bergen, Norway, ⁵Department of Clinical Science, University of Bergen, Bergen, Norway, ⁶Department of Clinical Science, Broegelmann Research Laboratory, University of Bergen, Bergen, Norway, ⁷Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK, Newcastle-Upon-Tyne, United Kingdom, ⁸Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-Upon-Tyne, UK, Newcastle-Upon-Tyne, United Kingdom, ⁹Dept of Rheumatology, Skane University Hospital Malmo, Lund University, Malmö, Sweden, ¹⁰Department of Rheumatology, Skåne University Hospital, Malmö, Sweden, Lund, Sweden, ¹¹Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹²Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden, ¹³Rheumatology, Department of Medical Sciences, Uppsala University, Sweden, Uppsala, Sweden, ¹⁴Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: GWAS, Sjogren's syndrome and fatigue

Session Information

Date: Sunday, November 5, 2017

Title: Genetics, Genomics and Proteomics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Fatigue is common in primary Sjögren`s syndrome (pSS), but the mechanisms that lead to fatigue are not fully understood. We hypothesized that there is a genetic basis for fatigue, and that specific gene-variants (single nucleotide polymorphisms – SNPs) influence the severity of fatigue. To investigate this further we performed a genome wide association study (GWAS) of 367 Scandinavian pSS patients.

Methods:

PSS patients from 4 sites in Norway and Sweden were collected through the Scandinavian Sjögren’s syndrome network. Genotyping was performed at the SNP&SEQ platform, Uppsala University, Sweden using the Illumina Human OmniExpressExome array. All included cases fulfilled the American-European Classification Criteria for pSS. Fatigue was assessed using the fatigue Visual Analogue Scale or the European Sjøgren`s Syndrome Patient Reported Index. Imputation was performed using SHAPEIT2 and IMPUTE2. After genotype and sample quality control and imputation a total of 365 samples and 4 966 159 SNPs remained for analysis. A linear regression analysis of fatigue scores versus minor alleles was performed.

Results:

The pSS patients were 92% females, mean age 57 years with a median fatigue score of 66 (range 0-100). Our analysis revealed five SNPs exceeding the genome wide significance (GWS) threshold of p=5E-8 with a beta coefficient of 12.8. All five SNPs were in linkage disequilibrium and two of the SNPs, rs7626469 and rs73182503, were in the gene Receptor Transporter Protein 4 (RTP4), in which the minor allele was associated with less fatigue. RTP4 encodes a Golgi chaperone, involved in the cell surface expression of opioid receptors. In addition, 58 SNPs in 4 genes (Endoplasmatic Reticulum to Nucleus Signaling 1 (ERN1), Long intergenic non-protein coding RNA 1553 (LINC01553), Long intergenic non-protein coding RNA 1184 (LINC01184) and (RP11-15I11.2) reached a suggestive significance level (p<1E-5).

Conclusion:

We identified genetic variants in RTP4 exceeding the GWS level for association with fatigue. Notably, this gene encodes a protein involved in pain processing. Pain is known to influence fatigue, and this finding could point to a possible molecular explanation. The present study is the largest GWAS of fatigue in autoimmune disease, and adds further evidence to a genetic regulation of fatigue.

Disclosure: K. Norheim, None; A. Alexsson, None; J. Imgenberg-Kreuz, None; J. G. Brun, None; R. Jonsson, None; W. F. Ng, None; E. Theander, None; T. Mandl, None; K. L. Sivils, None; L. Rönnblom, None; G. Nordmark, None; R. Omdal, None.

To cite this abstract in AMA style:

Norheim K, Alexsson A, Imgenberg-Kreuz J, Brun JG, Jonsson R, Ng WF, Theander E, Mandl T, Sivils KL, Rönnblom L, Nordmark G, Omdal R. Genetic Determinants of Fatigue in Primary Sjögren`s Syndrome – a Genome Wide Association Study [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/genetic-determinants-of-fatigue-in-primary-sjogrens-syndrome-a-genome-wide-association-study/. Accessed .

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