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Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes

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Abstract

We investigated the Nco I restriction fragment length polymorphism (RFLP) of the tumor necrosis factor beta (TNFB) gene in 173 patients with systemic lupus erythematosus (SLE), 192 unrelated healthy controls, and eleven panel families, all of German origin. The phenotype frequency of the TNFB*1 allele was significantly increased in patients compared to controls (63.6% vs 47.1%, RR = 1.96, p <0.002). The results of a two-point haplotype statistical analysis between TNFB and HLA alleles show that there is linkage disequilibrium between TNFB*1 and HLA-A1, Cw7, B8, DR3, DQ2, and C4A DE. The frequency of TNFB*1 was compared in SLE patients and controls in the presence or absence of each of these alleles. TNFB*1 is increased in patients over controls only in the presence of the mentioned alleles. Therefore, the whole haplotype A1, Cw7, B8, TNFB*1, C4A DE, DR3, DQ2 is increased in patients and it cannot be determined which of the genes carried by this haplotype is responsible for the susceptibility to SLE. In addition, two-locus associations were analyzed in 192 unrelated healthy controls for TNFB and class I alleles typed by serology, and for TNFB and class II alleles typed by polymerase chain reaction/oligonucleotide probes. We found positive linkage disequilibrium between TNFB*1 and the following alleles: HLA-A24, HLA-B8, DRB1*0301, DRB1*1104, DRB1*1302, DQA1*0501, DQB1*0201, DQB1*0604, and DPB1*0101. TNFB*2 is associated with HLA-B7, DRB1*1501, and DQB1*0602.

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References

  • Abraham, L. J., Du, D. C., Zahedi, K., Dawkins, R. L., and Whitehead, A. G. Haplotypic polymorphisms of the TNFB gene. Immunogenetics 33:50–53, 1991

    Google Scholar 

  • Andreas, A., Chandanayingyong, D., Attatippaholkum, W., Sirikong, M., Klaythong, R., Keller, E., and Albert, E. D. Unusual HLA-DR/DQ haplotypes: two different breakpoints in two different DR2-DQw3 haplotypes. Immunogenetics 30: 141–144, 1989

    Google Scholar 

  • Arnold, A. and Albert E. D. Computer Programm zur Berechnung von Haplotypfrequenzen des HLA-Systems. In Proceedings of the 7th ISBN, pp. 407–415, 1978

  • Badenhoop, K., Schwartz, G., Trowsdale, J., Lewis, V., Usadel, K. H., Gale, E. A. M., and Bottazzo, G. F. TNF-α gene polymorphisms in Type I (insulin dependent) diabetes mellitus. Diabetologia 32: 445–448, 1989

    Google Scholar 

  • Baur, M. P. and Danilovs, J. A. Population analysis of HLA-A,B,C,DR and other genetic markers. In P. I. Terasaki (ed.): Histocompatibility Testing 1980, pp. 955–1004, UCLA Tissue Typing Laboratory, Los Angeles, 1980

    Google Scholar 

  • Bettinotti, M. P. Untersuchungen an zwei mit dem Systemischen Lupus Erythematosus assoziierten HLA-Haplotypen: Dissertation (Humanbiologie) der Medizinischen Fakultät der Ludwig-Maximilians-Universität München, 1992

  • Dawkins, R. L., Leaver, A., Cameron, P. U., Martin, E., Kay, P. H., and Christiansen, F. T. Some disease-associated ancestral haplotypes carry a polymorphism of TNF. Hum Immunol 26: 91–97, 1989

    Google Scholar 

  • Fugger, L., Morling, N., Ryder, L. P., Georgsen, J., Jakobsen, B. K., Svejgaard, A., Andersen, V., Oxholm, P., Pedersen, F. K., Friis, J., and Halberg, P. NcoI restriction fragment length polymorphism (RFLP) of the tumor necrosis factor (TNFα) region in four autoimmune diseases. Tissue Antigens 34: 17–22, 1989

    Google Scholar 

  • Goeddel, D. V., Aggarwal, B. B., Gray, P. W., Leung, D. W., Nedwin, G. E., Palladino, M. A., Patton, J. S., Pennica, D., Shepard, H. M., Sugarman, B. J., and Wong, G. H. W. Tumor necrosis factors: gene structure and biological activities. Cold Spring Harbor Symposia on Quantative Biology, LI: 597–609, 1986

    Google Scholar 

  • Grumet, F. C., Coukell, A., Bodmer, J. G., Bodmer, W. F., and McDevitt, H. Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. N Engl J Med 285: 193–196, 1971

    Google Scholar 

  • Hartung, K., Fontana, A., Klar, M., Krippner, H., Jörgens, K., Lang, B., Peter, H. H., Pichler, W. J., Schendel, D., Robin-Winn, M., and Deicher, H. Association of class I, II and III MHC gene products with systemic lupus erythematosus. Rheumatol Int 9: 13–18, 1989

    Google Scholar 

  • Hartung, K., Coldewey, R., Krapf, F., Lang, B., Specker, Ch., Schendel, D., Schneider, P., Seuchter, S., Stangel, W., Albert, E., and Deicher, H., and the members of the Deutsche SLE-Multizenter Studie. Hetero- and homozygosity of MHC class II gene products in systemic lupus erythematosus. Tissue Antigens 38: 165–168, 1991

    Google Scholar 

  • Hartung, K., Baur, M. P., Coldewey, R., Kalden, J. R., Lakomek, H. J., Peter, H. H., Schendel, D., Schneider, P. M., Seuchter, S. A., Stangel, W., and Deicher, H. R. G., and the members of the SLE Multicenter Study Group. MHC-haplotypes and complement C4-alleles in systemic lupus erythematosus — Results of a multicenter study. J Clin Invest, in press, 1992.

  • Keller, E., Andreas, A., Scholz, S., Dörr, H. C., Knorr, D., and Albert, E. D. Prenatal Diagnosis of 21-Hydroxylase Deficiency by RFLP analysis of the 21-hydroxylase, complement C4 and HLA class II genes. Prenatal Diagnosis 11: 827–840, 1991

    Google Scholar 

  • Messer, G., Spengler, U., Jung, M. C., Honold, G., Blömer, K., Pape, G. R., Riethmüller, G., and Weiss, E. H. Polymorphic structure of the tumor necrosis factor (TNF) locus. An NcoI polymorphism in the first intron of the human TNF-β gene correlates with a variant amino acid in position 26 and a reduced level of TNF-β production. J Exp Med 173: 209–215, 1991a

    Google Scholar 

  • Messer, G., Spengler, U., Jung, M. C., Honold, G., Eisenburg, J., Scholz, S., Albert, E. D., Pape, G. R., Riethmüller, G., and Weiss, E. H. Allelic variation in the TNF-beta gene does not explain the low TNF-beta response in patients with primary biliary cirrhosis. Scand J Immunol 34: 735–740, 1991b

    Google Scholar 

  • Miller, S. A., Dykes, D. D., and Polesky, H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16: 1215, 1988

    CAS  PubMed  Google Scholar 

  • Nedospasov, S. A., Shakhov, A. N., Turetskaya, R. L., Mett, V. A., Azizov, M. M., Georgiev, G. P., Kowliko, V. G., Dobzynin, V. N., Filippov, S. A., Bystiov, N. S., Boldyeva, E. F., Chuvpilo, S. A., Chumakov, A. M., Shingarova, L. N., and Ovchinmikov, Y. A. Tandem arrangement of genes coding for tumor necrosis factor (TNF-α) and lymphotoxin (TNF-ß) in the human genome. Cold Spring Harbor Symposia on Quantitative Biology LI: 611–624, 1986

    Google Scholar 

  • Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., McShane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., and Winchester, R. J. 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: 1271–1277, 1982

    CAS  PubMed  Google Scholar 

  • Waters, H., Konrad, R., and Walford, R. L. The distribution of HL-A histocompatibility factors and genes in patients with systemic lupus erythematosus. Tissue Antigens 1: 68–73, 1971

    Google Scholar 

  • Webb, G. C. and Chaplin, D. D. Genetic variability at the human tumor necrosis factor loci. J Immunol 145: 1278, 1990

    Google Scholar 

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Authors and Affiliations

  1. Immunogenetics Laboratory, University of Munich, Germany

    Maria P. Bettinotti, Elisabeth Keller & Ekkehard D. Albert

  2. University of Hannover, Germany

    Klaus Hartung & Helmuth Deicher

  3. Department of Dermatology, University of Munich, Germany

    Gerald Messer

  4. Department of Anthropology and Human Genetics, University of Munich, Germany

    Elisabeth H. Weiss

Authors
  1. Maria P. Bettinotti
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  2. Klaus Hartung
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  3. Helmuth Deicher
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  4. Gerald Messer
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  5. Elisabeth Keller
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  6. Elisabeth H. Weiss
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  7. Ekkehard D. Albert
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Additional information

This study was supported by grants from the Federal Ministry of Research and Technology (BMFT/DFVLR, 01 VM 8608/9), the German Academic Exchange Service (DAAD, 322/501/014/0), and SFB (217).

This work is part of the doctoral thesis of M. P. Bettinotti.

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Bettinotti, M.P., Hartung, K., Deicher, H. et al. Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes. Immunogenetics 37, 449–454 (1993). https://doi.org/10.1007/BF00222469

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  • DOI: https://doi.org/10.1007/BF00222469

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