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Korotkova, M.; Daha, N.A.; Seddighzadeh, M.; Ding, B.; Catrina, A.I.; Lindblad, S.; ... ; Padyukov, L. (2011)

Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis

Article / Letter to editor
Microsomal PGE synthase 1 (mPGES-1) is the terminal enzyme in the induced state of prostaglandin E-2 (PGE(2)) 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...Show moreMicrosomal PGE synthase 1 (mPGES-1) is the terminal enzyme in the induced state of prostaglandin E-2 (PGE(2)) 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. European Journal of Human Genetics (2011) 19, 908-914; doi:10.1038/ejhg.2011.50; published online 30 March 2011Show less
mPGES-1 gene polymorphism rheumatoid arthritis gender mice lacking cox-2 gene risk polymorphisms susceptibility identification prostanoids expression pathway target
All authors
Korotkova, M.; Daha, N.A.; Seddighzadeh, M.; Ding, B.; Catrina, A.I.; Lindblad, S.; Huizinga, T.W.J.; Toes, R.E.M.; Alfredsson, L.; Klareskog, L.; Jakobsson, P.J.; Padyukov, L.
Date
2011-08-31
Journal
European Journal of Human Genetics
Volume
19
Issue
8
Pages
908 - 914
DOI
doi:10.1038/ejhg.2011.50