Vol.19 No.2

Original Article

Combining effects of polymorphism of tumor necrosis factor α 5′-flanking region and HLA-DRB1 on radiological progression in patients with rheumatoid arthritis

Authors

Naomi Ichikawa1 , Shigeru Kotake1 , Masayuki Hakoda2 , Kenshi Higami3 , Aya Kawasaki5 , Takefumi Furuya1 , Yuki Nanke1 , Naoyuki Tsuchiya5 , Katsushi Tokunaga4 , Naoyuki Kamatani1

  • Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan
  • Department of Nutritional Sciences, Faculty of Human Ecology, Yasuda Women’s University, 6-13-1 Ando, Asaminami-ku, Hiroshima 731-0153, Japan
  • Higami Hospital, 701 Kuzumoto-cho, Kashihara, Nara 634-0007, Japan
  • Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
  • Doctoral Program in Social and Environmental Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki, 305-8575, Japan
Received:

21 May 2008

Accepted:

29 September 2008

Published online:

12 November 2008

Full Text

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Abstract

We examined whether polymorphisms upstream of the TNF-α gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen’s score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5′-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE-) showed the lowest progression of Larsen’s score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE-, U02-SE+, and U02-SE- groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.

Key words

Polymorphism - Rheumatoid arthritis - Tumor necrosis factor