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Functional Analysis of a Human Tumor Necrosis Factor α (TNF-α) Promoter Polymorphism Related to Joint Damage in Rheumatoid Arthritis

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Abstract

Background

Functional heterogeneity in the tumor necrosis factor α (TNF-α) gene may be responsible for the TNF-α response in infectious and autoimmune diseases. Recently, the TNF-238 promoter polymorphism was observed as being associated with a more destructive disease in rheumatoid arthritis (RA). To determine the relation between TNF-238 and disease progression, the extent of joint destruction in a cohort of 101 RA patients followed for 12 years was analyzed. Furthermore, we have attempted to link this polymorphism to TNF-α gene transcription in monocytes and lymphocytes in vitro.

Patients, Materials, and Methods

The extent of joint destruction determined on X-rays of hands and feet assessed after 0, 3, 6, and 12 years was compared with TNF-238 genotypes. Functional consequences of TNF-α gene polymorphisms using reporter gene constructs were analyzed in cells of the monocyte and lymphocyte lineage by means of transient transfection systems.

Results

The rate of joint damage in -238GA patients was lower than that in the -238GG patients, independent of HLA-DR4. Damage after 12 years was 76 ± 30 for the -238GA versus 126 ± 13 for the -238GG patients as determined by the van der Heijde’s modification of Sharp’s method. Furthermore, TNF-238A was found to be in linkage disequilibrium with an additional polymorphism at position −376. Functional assays revealed no significant differences in the level of inducible reporter gene expression between the TNF-238/-376 promoter constructs in the cell types tested.

Conclusion

In a prospective study, we show that the TNF-238GG genotype contributes to progression of joint destruction in RA, independent of the presence of HLA-DR4. However, in vitro transfection assays indicate that TNF-238A by itself or in combination with TNF-376A is not likely to be of direct functional relevance for transcriptional activation. Therefore, these polymorphisms may serve as markers for additional polymorphisms in the TNF/LT locus or neighboring genes that may influence disease severity.

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Acknowledgments

We are grateful to Dr. Wiepke Drossaers-Bakker for establishing the cohort organization, Drs. Koos Zwinderman and Ingrid Meulenbelt for statistical assistance, and Dr. Irina Udalova for providing us with the −1173/ + 130 TNF-α promoter/enhancer constructs. This project was funded with Federal funds from Het nationaal Reumafonds and the National Cancer Institute, National Institutes of Health, under Contract no. N01-CO-56000.

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Author notes

  1. Brigitta M. N. Brinkman

    Present address: Center for Blood Research, Boston, MA, USA

Authors and Affiliations

  1. Department of Rheumatology, Leiden University Medical Center, Building 1, C4R, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Eric L. Kaijzel, Michiel V. van Krugten, Brigitta M. N. Brinkman, Tom W. J. Huizinga, Tahar van der Straaten, J. Mieke W. Hazes, Ferdinand C. Breedveld &  Cornelis L. Verweij

  2. Institute for Immunology, University of Munich, Munich, Germany

    H. W. Loems Ziegler-Heitbrock

  3. Engelhardt Institute of Molecular Biology and Belozersky Institute of Physico-Chemical Biology, Moscow, Russia

    Sergei A. Nedospasov

  4. Intramural Research Support Program, SAIC Frederick, National Cancer Institute—Frederick Cancer Research and Development Center, Frederick, Maryland, USA

    Sergei A. Nedospasov

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  1. Eric L. Kaijzel
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Correspondence to Cornelis L. Verweij.

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Kaijzel, E.L., van Krugten, M.V., Brinkman, B.M.N. et al. Functional Analysis of a Human Tumor Necrosis Factor α (TNF-α) Promoter Polymorphism Related to Joint Damage in Rheumatoid Arthritis. Mol Med 4, 724–733 (1998). https://doi.org/10.1007/BF03401767

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