Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFα gene and HLA genes

Yukiji Date, Naoko Seki, Shintaro Kamizono, Takafumi Higuchi, Tomoshige Hirata, Koichiro Miyata, Masahiko Ohkuni, Osamu Tatsuzawa, Shumpei Yokota, Kunitaka Joo, Kohji Ueda, Takehiko Sasazuki, Akinori Kimura, Kyogo Itoh, Hirohisa Kato

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Abstract

Objective. To study polymorphisms in the 5'-flanking promoter/enhancer region of the tumor necrosis factor α (TNFα) gene and in the coding regions of HLA class I and class II genes, in order to better understand the genetic background of juvenile rheumatoid arthritis (JRA). Methods. One hundred eleven Japanese JRA patients (50 with systemic disease, 29 with pauciarticular disease, and 32 with polyarticular disease) and 575 healthy Japanese subjects were examined for the allele frequencies of the TNFα, HLA- A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method. Results. The frequencies of the polymorphic allele at positions -1,031 (T to C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNFα gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, were significantly higher than in the healthy controls. The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were significantly higher than in controls. Linkage analysis showed that the presence of both the TNFα -857T allele and DRB1*0405 yielded a significantly increased odds ratio (3.84), while the presence of only 1 of them did not yield a high odds ratio (0.87 and 1.58). Conclusion. The -1,031C/-863A allele and the -857T allele of the TNFα gene, both of which are related to high production of tumor necrosis factor α, are associated with systemic JRA. The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA.

Original languageEnglish
Pages (from-to)2577-2582
Number of pages6
JournalArthritis and rheumatism
Volume42
Issue number12
DOIs
Publication statusPublished - Dec 1 1999

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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    Date, Y., Seki, N., Kamizono, S., Higuchi, T., Hirata, T., Miyata, K., Ohkuni, M., Tatsuzawa, O., Yokota, S., Joo, K., Ueda, K., Sasazuki, T., Kimura, A., Itoh, K., & Kato, H. (1999). Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFα gene and HLA genes. Arthritis and rheumatism, 42(12), 2577-2582. https://doi.org/10.1002/1529-0131(199912)42:12<2577::AID-ANR10>3.0.CO;2-O