Fatigue is prevalent and disabling in primary Sjögren’s syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS <50 denominated “low fatigue” (n = 53) and VAS ≥50 denominated “high fatigue” (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Jonsson R, Vogelsang P, Volchenkov R, Espinosa A, Wahren-Herlenius M, Appel S (2011) The complexity of Sjögren’s syndrome: novel aspects on pathogenesis. Immunol Lett 141:1–9
Reveille JD, Wilson RW, Provost TT, Bias WB, Arnett FC (1984) Primary Sjögren’s syndrome and other autoimmune diseases in families. Prevalence and immunogenetic studies in six kindreds. Ann Intern Med 101:748–756
Cruz-Tapias P, Rojas-Villarraga A, Maier-Moore S, Anaya JM (2012) HLA and Sjögren’s syndrome susceptibility. A meta-analysis of worldwide studies. Autoimmun Rev 11:281–287
Bolstad AI, Le Hellard S, Kristiansdottir G et al (2012) Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjögren’s syndrome in Scandinavian samples. Ann Rheum Dis 71:981–988
Miceli-Richard C, Comets E, Loiseau P, Puechal X, Hachulla E, Mariette X (2007) Association of an IRF5 gene functional polymorphism with Sjögren’s syndrome. Arthritis Rheum 56:3989–3994
Nordmark G, Kristjansdottir G, Theander E et al (2009) Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren’s syndrome. Genes Immun 10:68–76
Korman BD, Alba MI, Le JM et al (2008) Variant form of STAT4 is associated with primary Sjögren’s syndrome. Genes Immun 9:267–270
Appel S, Le Hellard S, Bruland O et al (2011) Potential association of muscarinic receptor 3 gene variants with primary Sjögren’s syndrome. Ann Rheum Dis 70:1327–1329
Nordmark G, Kristjansdottir G, Theander E et al (2011) Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren’s syndrome. Genes Immun 12:100–109
Meijer JM, Meiners PM, Huddleston Slater JJ et al (2009) Health-related quality of life, employment and disability in patients with Sjögren’s syndrome. Rheumatology (Oxford) 48:1077–1082
Bowman SJ (2008) Patient-reported outcomes including fatigue in primary Sjögren’s syndrome. Rheum Dis Clin North Am 34:949–962
Van Hoogmoed D, Fransen J, Bleijenberg G, van Riel P (2010) Physical and psychosocial correlates of severe fatigue in rheumatoid arthritis. Rheumatology (Oxford) 49:1294–1302
Ng WF, Bowman SJ (2010) Primary Sjögren’s syndrome: too dry and too tired. Rheumatology (Oxford) 49:844–853
Burgos PI, Alarcon GS, McGwin G Jr, Crews KQ, Reveille JD, Vila LM (2009) Disease activity and damage are not associated with increased levels of fatigue in systemic lupus erythematosus patients from a multiethnic cohort: LXVII. Arthritis Rheum 61:1179–1186
Haldorsen K, Bjelland I, Bolstad AI, Jonsson R, Brun JG (2011) A five-year prospective study of fatigue in primary Sjögren’s syndrome. Arthritis Res Ther 13:R167
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 121:953–959
Smith AK, Fang H, Whistler T, Unger ER, Rajeevan MS (2011) Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology 64:183–194
Kaushik N, Fear D, Richards SC et al (2005) Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol 58:826–832
Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A (2006) Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis 6:15
Kerr JR, Petty R, Burke B et al (2008) Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Infect Dis 197:1171–1184
Vitali C, Bombardieri S, Jonsson R et al (2002) Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558
Wolfe F (2004) Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients. J Rheumatol 31:1896–1902
Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Gøransson LG, Haldorsen K, Brun JG et al (2011) The point prevalence of clinically relevant primary Sjögren’s syndrome in two Norwegian counties. Scand J Rheumatol 40:221–224
Haitina T, Lindblom J, Renström T, Fredriksson R (2006) Fourteen novel human members of mitochondrial solute carrier family 25 (SLC25) widely expressed in the central nervous system. Genomics 88:779–790
Kato T Jr, Gotoh Y, Hoffmann A, Ono Y (2008) Negative regulation of constitutive NF-κB and JKN signaling by PKN1-mediated phosphorylation of TRAF1. Genes Cells 13:509–520
Myhill S, Booth NE, McLaren-Howard J (2009) Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2:1–16
Fulle S, Mecocci P, Fano G et al (2000) Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med 29:1252–1259
Raffaello A, Rizzuto R (2011) Mitochondrial longevity pathways. Biochim Biophys Acta 1813:260–268
Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ (2005) Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med 39:584–589
Nicolson GL, Conklin KA (2008) Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy. Clin Exp Metastasis 25:161–169
Harboe E, Tjensvoll AB, Vefring HK, Goransson LG, Kvaloy JT, Omdal R (2009) Fatigue in primary Sjögren’s syndrome–a link to sickness behaviour in animals? Brain Behav Immun 23:1104–1108
Norheim KB, Harboe E, Gøransson L, Omdal R (2012) Interleukin-1 inhibition and fatigue in primary Sjögren’s syndrome—a double blind, randomised clinical trial. PLoS One 7:e31123
Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–140
Norheim KB, Jonsson G, Omdal R (2011) Biological mechanisms of chronic fatigue. Rheumatology (Oxford) 50:1009–1018
Landmark-Hoyvik H, Reinertsen KV, Loge JH, Fossa SD, Borresen-Dale AL, Dumeaux V (2009) Alterations of gene expression in blood cells associated with chronic fatigue in breast cancer survivors. Pharmacogenomics J 9:333–340
Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW (2011) Fatigue and gene expression in human leukocytes: increased NF-kappaB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Brain Behav Immun 25:147–150
Collado-Hidalgo A, Bower JE, Ganz PA, Irwin MR, Cole SW (2008) Cytokine gene polymorphisms and fatigue in breast cancer survivors: early findings. Brain Behav Immun 22:1197–1200
Reinertsen KV, Grenaker Alnaes GI, Landmark-Hoyvik H et al (2011) Fatigued breast cancer survivors and gene polymorphisms in the inflammatory pathway. Brain Behav Immun 25:1376–1383
We thank Per Lundmark for selecting tag-SNPs. This work was supported by an internal research grant from Stavanger University Hospital to KBN, Grant number N/A.
Conflict of interest
The authors declare no conflict of interest.
About this article
Cite this article
Norheim, K.B., Le Hellard, S., Nordmark, G. et al. A possible genetic association with chronic fatigue in primary Sjögren’s syndrome: a candidate gene study. Rheumatol Int 34, 191–197 (2014). https://doi.org/10.1007/s00296-013-2850-9
- Primary Sjögren’s syndrome
- Genetic association