title: Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis.
abstract: Levels of soluble tumour necrosis factor receptors (sTNFRs) are elevated in the circulation of patients with rheumatoid arthritis (RA). Although these receptors can act as natural inhibitors of tumour necrosis factor-alpha, levels of sTNFRs in RA appear to be insufficient to prevent tumour necrosis factor-alpha induced inflammation. The factors that regulate circulating levels of sTNFRs are unclear, but polymorphisms in the tumour necrosis factor receptor genes may play a role. We investigated the relationship between polymorphisms in the tumour necrosis factor receptor I (TNF-RI) and II (TNF-RII) genes and levels of sTNFRs in two groups of Caucasian RA patients: one with early (disease duration < or = 2 years; n = 103) and one with established disease (disease duration > or = 5 years; n = 151). PCR restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNF-RI gene and the T676G polymorphism in TNF-RII. Levels of sTNFRs were measured using ELISA. We also isolated T cells from peripheral blood of 58 patients with established RA with known TNF-R genotypes, and release of sTNFRs into the culture medium was measured in cells incubated with or without phytohaemagglutinin. Serum levels of the two sTNFRs (sTNF-RI and sTNF-RII) were positively correlated in both populations, and the level of each sTNFR was significantly higher in the patients with established disease (P < 0.0001). Multiple regression analyses corrected for age, sex and disease duration revealed a significant trend toward decreasing sTNF-RI and sTNF-RII levels across the TNF-RII genotypes (TT > TG > GG) of patients with established disease (P for trend = 0.01 and P for trend = 0.03, respectively). A similar nonsignificant trend was seen for early disease. No relationship with the TNF-RI A36G polymorphism was observed. sTNFRs released by isolated T cells exhibited a similar trend toward decreasing levels according to TNF-RII genotype, although only the association with levels of sTNF-RII was significant. Strong correlations were found between levels of circulating sTNFRs and levels released by T cells in vitro. Our data indicate that the T676G polymorphism in TNF-RII is associated with levels of sTNFRs released from peripheral blood T cells, and with circulating levels of sTNFR in patients with RA.
authors.affiliation: Staffordshire Rheumatology Centre, University Hospital of North Staffordshire, Stoke-on-Trent, UK. jrglossop@hotmail.com
authors.forename: John R
authors.initials: JR
authors.lastname: Glossop
authors.forename: Peter T
authors.initials: PT
authors.lastname: Dawes
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Nixon
authors.forename: Derek L
authors.initials: DL
authors.lastname: Mattey
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D005260:Female; D006304:Health Status; D006801:Humans; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood* / Q000235:genetics*; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
chemical_list: D010835:Phytohemagglutinins; D047889:Receptors, Tumor Necrosis Factor, Type II; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins