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

Marina Korotkova (1) , Nina Daha (1) , Maria Seddighzadeh (1) , Bo Ding Ding (1) , Anca I Catrina (1) , Staffan Lindblad (1) , Tom Huizinga (1) , Rene Toes (1) , Lars Alfredsson (1) , Lars Klareskog (1) , Per-Johan Jakobsson (1) , Leonid Padyukov (1)

1 Rheumatology Unit, Department of Medicine

Microsomal PGE synthase 1 (mPGES-1) is the terminal enzyme in induced state of prostaglandin E2 (PGE2) synthesis and constitutes a therapeutic target for rheumatoid arthritis (RA) treatment. We examined the role of the 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 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 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 1.28 (95%CI 1.09-1.51). Several PTGES SNPs were associated with earlier onset of disease or with higher DAS28 in women with RA. The 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 up-regulation of mPGES-1 at the sites of inflammation. Genetically predisposed individuals may develop earlier and more active disease due to this mechanism.

Mots clés: rheumatoid arthritis; gene polymorphism; mPGES-1

Marina Korotkova, Nina Daha, Maria Seddighzadeh, Bo Ding Ding, Anca I Catrina, et al.. Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis.. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.50⟩. ⟨hal-00627920⟩