title: Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis.
abstract: 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 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.
authors: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors: Marina
authors: M
authors: Korotkova
authors: Nina A
authors: NA
authors: Daha
authors: Maria
authors: M
authors: Seddighzadeh
authors: Bo
authors: B
authors: Ding
authors: Anca I
authors: AI
authors: Catrina
authors: Staffan
authors: S
authors: Lindblad
authors: Tom W J
authors: TW
authors: Huizinga
authors: Rene E M
authors: RE
authors: Toes
authors: Lars
authors: L
authors: Alfredsson
authors: Lars
authors: L
authors: Klareskog
authors: Per-Johan
authors: PJ
authors: Jakobsson
authors: Leonid
authors: L
authors: Padyukov
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic; D000071876:Prostaglandin-E Synthases; D012737:Sex Factors; D013548:Sweden / Q000453:epidemiology; D013583:Synovial Membrane / Q000473:pathology
chemical_list: D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases