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Ann Rheum Dis. 2007 December; 66(12): 1684–1685.
PMCID: PMC2095302

Tumour necrosis factor receptor 2 (TNFRSF1B) association study in Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is a complex disease involving both genetic and environmental factors. Among the genetic susceptibility factors, HLA‐DRB1 has been extensively studied as a strong candidate gene and the association of HLADRB1*0301 (DR3) with pSS has been frequently reported among Caucasians.1,2 As the Tumour Necrosis Factor α (TNFα) gene is located within the HLA region, its contribution to disease susceptibility has also been studied. We have previously reported a significant association of TNF‐308A allele with pSS, in strong linkage disequilibrium with HLA‐DRB1*03.3 This association was restricted to patients with anti‐SSB antibodies. TNF exerts its action through two cell surface receptors, TNF receptors 1 and 2 (TNFR1 and TNFR2, 55 and 75 kDa respectively). Due to the functional interaction between TNF and TNFR2, we considered this receptor (also named TNFRSF1B) as another interesting candidate gene for the genetic susceptibility to pSS. TNFR2 T676G polymorphism replacing a methionine by an arginine (TNFR2 196 M/R) is functional as the cytotoxic activity induced by TNFR2 196R (TNFR2 696 G allele) is increased.4 Moreover, TNFR2 T676G polymorphism has been previously associated with the genetic susceptibility to other autoimmune diseases: familial, but not sporadic, rheumatoid arthritis (RA)5 and systemic lupus erythematosus (SLE).6

We carried out a case–control association study of TNFR2 T676G polymorphism among 119 unrelated patients with pSS according to European–American consensus group (46 patients without autoantibodies (Ab), 33 patients with anti‐SSA Ab only, 40 patients with anti‐SSA and anti‐SSB Ab) and 95 healthy controls. Both patients and controls were of Caucasian origin. TNFR2 T676G polymorphism was genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis (Nla III).

No significant differences in allele and genotype frequencies of TNFR2 T676G polymorphism were detected between patients with pSS and controls (Table 11).). TNFR2 T676G polymorphism was not involved in the genetic predisposition to a specific pattern of autoantibody secretion (p = 0.61). No association was found with extraglandular involvement (p = 0.34). Interestingly, there was a trend in favour of an association with joint involvement (arthritis and arthralgia) (p = 0.06). An epistatic effect between TNF ‐308A/G and TNFR2 T676G polymorphisms was then looked for, but not evidenced, among 55 pSS patients.

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Table 1 Allelic and genotypic frequencies of TNFR2 T676G polymorphism in 119 patients with pSS and 95 controls

This study failed to demonstrate an association of TNFR2 T676G polymorphism with pSS. These results, together with the lack of efficacy of infliximab in pSS7 rather suggest a poor involvement of the TNF/TNF receptor system in the susceptibility to pSS.

To date, among rheumatic diseases, TNFR2 T676G polymorphism association with lupus led to conflicting results.4,6,8,9 A recent case–control study performed in an Asian population of patients also failed to demonstrate any association of TNFR2T676G polymorphism with SLE.10 However, this study also provided a metaanalysis of seven case–control studies in eight different ethnic populations. Stratification by ethnicity revealed a significant association among Asians while the effect of TNFR2T676G polymorphism on SLE was not significant in two case‐control studies involving Caucasians (OR = 0.99, 95%CI = 0.68 to 1.45; p = 0.96). Thus, as observed among Caucasian SLE patients, our study provides evidence suggesting that TNFR2T676G polymorphism is not involved in the genetic predisposition to pSS in French Caucasian patients.


Competing interests: None.


1. Arnett F C, Hamilton R G, Reveille J D, Bias W B, Harley J B, Reichlin M. Genetic studies of Ro (SS‐A) and La (SS‐B) autoantibodies in families with systemic lupus erythematosus and primary Sjogren's syndrome. Arthritis Rheum 1989. 32413–419.419 [PubMed]
2. Bolstad A I, Wassmuth R, Haga H J, Jonsson R. HLA markers and clinical characteristics in Caucasians with primary Sjogren's syndrome. J Rheumatol 2001. 281554–1562.1562 [PubMed]
3. Gottenberg J E, Busson M, Loiseau P, Dourche M, Cohen‐Solal J, Lepage V. et al Association of transforming growth factor beta1 and tumor necrosis factor alpha polymorphisms with anti‐SSB/La antibody secretion in patients with primary Sjogren's syndrome. Arthritis Rheum 2004. 50570–580.580 [PubMed]
4. Morita C, Horiuchi T, Tsukamoto H, Hatta N, Kikuchi Y, Arinobu Y. et al Association of tumor necrosis factor receptor type II polymorphism 196R with Systemic lupus erythematosus in the Japanese: molecular and functional analysis. Arthritis Rheum 2001. 442819–2827.2827 [PubMed]
5. Dieude P, Petit E, Cailleau‐Moindrault S, Osorio J, Pierlot C, Martinez M. et al Association between tumor necrosis factor receptor II and familial, but not sporadic, rheumatoid arthritis: evidence for genetic heterogeneity. Arthritis Rheum 2002. 462039–2044.2044 [PubMed]
6. Komata T, Tsuchiya N, Matsushita M, Hagiwara K, Tokunaga K. Association of tumor necrosis factor receptor 2 (TNFR2) polymorphism with susceptibility to systemic lupus erythematosus. Tissue Antigens 1999. 53527–533.533 [PubMed]
7. Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E. et al Inefficacy of infliximab in primary Sjogren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjogren's Syndrome (TRIPSS). Arthritis Rheum 2004. 501270–1276.1276 [PubMed]
8. Lee E B, Yoo J E, Lee Y J, Choi Y J, Park K S, Song Y W. Tumor necrosis factor receptor 2 polymorphism in systemic lupus erythematosus: no association with disease. Hum Immunol 2001. 621148–1152.1152 [PubMed]
9. Tsuchiya N, Kawasaki A, Tsao B P, Komata T, Grossman J M, Tokunaga K. Analysis of the association of HLA‐DRB1, TNFalpha promoter and TNFR2 (TNFRSF1B) polymorphisms with SLE using transmission disequilibrium test. Genes Immun 2001. 2317–322.322 [PubMed]
10. Horiuchi T, Kiyohara C, Tsukamoto H, Sawabe T, Furugo I, Yoshizawa S. et al A functional M196R polymorphism of tumor necrosis factor receptor type 2 is associated with systemic lupus erythematosus: A case‐control study and a meta‐analysis. Ann Rheum Dis 2007. 66320–324.324 [PMC free article] [PubMed]

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