Abstract
Microsomal PGE synthase 1 (mPGES-1) is the terminal enzyme in the induced state of prostaglandin E2 (PGE2) synthesis and constitutes a therapeutic target for rheumatoid arthritis (RA) treatment. We examined the role of the prostaglandin E synthase (PTGES) gene polymorphism in susceptibility to and severity of RA and related variations in the gene to its function. The PTGES gene polymorphism was analyzed in 3081 RA patients and 1900 controls from two study populations: Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the Leiden Early Arthritis Clinic (Leiden EAC). Baseline disease activity score (DAS28) was employed as a disease severity measure. mPGES-1 expression was analyzed in synovial tissue from RA patients with known genotypes using immunohistochemistry. In the Swedish study population, among women a significant association with risk for RA was observed for PTGES single-nucleotide polymorphisms (SNPs) in univariate analysis and for the distinct haplotype. These results were substantiated by meta-analysis of data from EIRA and Leiden EAC studies with overall OR 1.31 (95% confidence interval 1.11–1.56). Several PTGES SNPs were associated with earlier onset of disease or with higher DAS28 in women with RA. Patients with the genotype associated with higher DAS28 exhibited significantly higher mPGES-1 expression in synovial tissue. Our data reveal a possible influence of PTGES polymorphism on the pathogenesis of RA and on disease severity through upregulation of mPGES-1 at the sites of inflammation. Genetically predisposed individuals may develop earlier and more active disease owing to this mechanism.
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References
Klareskog L, Alfredsson L, Rantapaa-Dahlqvist S, Berglin E, Stolt P, Padyukov L : What precedes development of rheumatoid arthritis? Ann Rheum Dis 2004; 63 (Suppl 2): ii28–ii31.
Gao XJ, Olsen NJ, Pincus T, Stastny P : HLA-DR alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis. Arthritis Rheum 1990; 33: 939–946.
Moreno I, Valenzuela A, Garcia A, Yelamos J, Sanchez B, Hernanz W : Association of the shared epitope with radiological severity of rheumatoid arthritis. J Rheumatol 1996; 23: 6–9.
Raychaudhuri S : Recent advances in the genetics of rheumatoid arthritis. Curr Opin Rheumatol 2010; 22: 109–118.
Halushka MK, Halushka PV : Toward individualized analgesic therapy: functional cyclooxygenase 1 and 2 haplotypes. Clin Pharmacol Ther 2006; 79: 404–406.
Skarke C, Schuss P, Kirchhof A, Doehring A, Geisslinger G, Lotsch J : Pyrosequencing of polymorphisms in the COX-2 gene (PTGS2) with reported clinical relevance. Pharmacogenomics 2007; 8: 1643–1660.
Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B : Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci USA 1999; 96: 7220–7225.
Samuelsson B, Morgenstern R, Jakobsson P-J : Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 2007; 59: 207–224.
Kamei D, Yamakawa K, Takegoshi Y et al: Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin E synthase-1. J Biol Chem 2004; 279: 33684–33695.
Trebino C, Stock J, Gibbons C et al: Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci USA 2003; 100: 9044–9049.
Stichtenoth DO, Thoren S, Bian H, Peters-Golden M, Jakobsson PJ, Crofford LJ : Microsomal prostaglandin E synthase is regulated by proinflammatory cytokines and glucocorticoids in primary rheumatoid synovial cells. J Immunol 2001; 167: 469–474.
Korotkova M, Westman M, Gheorghe KR et al: Effects of antirheumatic treatments on the prostaglandin E2 biosynthetic pathway. Arthritis Rheum 2005; 52: 3439–3447.
Westman M, Korotkova M, af Klint E et al: Expression of microsomal prostaglandin E synthase in rheumatoid arthritis synovium. Arthritis Rheum 2004; 50: 1774–1780.
Hoeft B, Becker N, Deeg E, Beckmann L, Nieters A : Joint effect between regular use of non-steroidal anti-inflammatory drugs, variants in inflammatory genes and risk of lymphoma. Cancer Causes Control 2008; 19: 163–173.
Lemaitre RN, Rice K, Marciante K et al: Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke. Atherosclerosis 2009; 204: e58–e63.
Abraham JE, Harrington P, Driver KE et al: Common polymorphisms in the prostaglandin pathway genes and their association with breast cancer susceptibility and survival. Clin Cancer Res 2009; 15: 2181–2191.
Iwai N, Tago N, Yasui N et al: Genetic analysis of 22 candidate genes for hypertension in the Japanese population. J Hypertens 2004; 22: 1119–1126.
Arnett FC, Edworthy SM, Bloch DA et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.
Klareskog L, Stolt P, Lundberg K et al: A new model for an etiology of rheumatoid arthritis. Smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006; 54: 38–46.
van Aken J, van Bilsen JH, Allaart CF, Huizinga TW, Breedveld FC : The Leiden Early Arthritis Clinic. Clin Exp Rheumatol 2003; 21 (Suppl 31): S100–S105.
Plenge RM, Seielstad M, Padyukov L et al: TRAF1–C5 as a risk locus for rheumatoid arthritis — a genomewide study. N Engl J Med 2007; 357: 1199–1209.
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN : Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.
Helmersson J, Arnlov J, Axelsson T, Basu S : A polymorphism in the cyclooxygenase 1 gene is associated with decreased inflammatory prostaglandin F2alpha formation and lower risk of cardiovascular disease. Prostaglandins Leukot Essent Fatty Acids 2009; 80: 51–56.
Lee KH, Kim HS, El-Sohemy A, Cornelis MC, Uhm WS, Bae SC : Cyclooxygenase-2 genotype and rheumatoid arthritis. J Rheumatol 2006; 33: 1231–1234.
Yun HR, Lee SO, Choi EJ, Shin HD, Jun JB, Bae SC : Cyclooxygenase-2 polymorphisms and risk of rheumatoid arthritis in Koreans. J Rheumatol 2008; 35: 763–769.
The Wellcome Trust Case Control Consortium: Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.
Zhuang JJ, Morris AP : Assessment of sex-specific effects in a genome-wide association study of rheumatoid arthritis. BMC Proc 2009; 3 (Suppl 7): S90.
Olsson LM, Lindqvist AK, Kallberg H et al: A case-control study of rheumatoid arthritis identifies an associated single nucleotide polymorphism in the NCF4 gene, supporting a role for the NADPH-oxidase complex in autoimmunity. Arthritis Res Ther 2007; 9: R98.
Upadhyay R, Jain M, Kumar S, Ghoshal UC, Mittal B : Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squamous cell carcinoma. Mutat Res 2009; 663: 52–59.
Vogel U, Segel S, Dethlefsen C et al: Associations between COX-2 polymorphisms, blood cholesterol and risk of acute coronary syndrome. Atherosclerosis 2010; 1: 155–162.
Murphey LJ, Williams MK, Sanchez SC et al: Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer. Anal Biochem 2004; 334: 266–275.
Cheng Y, Wang M, Yu Y, Lawson J, Funk CD, Fitzgerald GA : Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 2006; 116: 1391–1399.
Sullivan JC, Sasser JM, Pollock DM, Pollock JS : Sexual dimorphism in renal production of prostanoids in spontaneously hypertensive rats. Hypertension 2005; 45: 406–411.
Francois H, Coffman TM : Prostanoids and blood pressure: which way is up? J Clin Invest 2004; 114: 757–759.
Audoly LP, Tilley SL, Goulet J et al: Identification of specific EP receptors responsible for the hemodynamic effects of PGE2. Am J Physiol 1999; 277: H924–H930.
Degousee N, Angoulvant D, Fazel S et al: c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes. J Biol Chem 2006; 281: 16443–16452.
Acknowledgements
We thank the RA patients and controls for participating in the study, and Eva Jemseby and Gul-Britt Almgren for invaluable contributions to the collection of data and maintenance of the EIRA database. This study is supported by the Swedish Research Council, Swedish Rheumatism Association, King Gustaf V 80 years Foundation, Swedish Society of Medicine, Karolinska Institutet Foundation, European Commission Sixth Framework Program Autocure and European Commission Seventh Framework Program Masterswitch.
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There is potential duality of interest since Dr M Korotkova was recently partially employed by Actar AB.
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Korotkova, M., Daha, N., Seddighzadeh, M. et al. Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis. Eur J Hum Genet 19, 908–914 (2011). https://doi.org/10.1038/ejhg.2011.50
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DOI: https://doi.org/10.1038/ejhg.2011.50
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