OHASHI Jun Graduate School of Medicine, The University of Tokyo, Assistant Professor, 大学院・医学系研究科, 助手 (80301141)
YAMAGUCHI Akihiro Faculty of Medicine Hospital, The University of Tokyo, Assistant Professor, 医学部・附属病院, 助手 (90261974)
HOHJOH Hirohko Graduate School of Medicine, The University of Tokyo, Assistant Professor, 大学院・医学系研究科, 助手 (60238722)
HONDA Zenichiro Facultyl of Medicine Hospital, The University of Tokyo, Lecturer, 医学部・附属病院, 講師 (70238814)
|Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2001: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1999: ¥6,900,000 (Direct Cost: ¥6,900,000)
The gain insight into the genetic background of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn's disease, two lines of studies were conducted. First, genomic polymorphisms were screened for candidate genes such as TNFR2, FCCR2B, CD28, CTLA-4, CD80, CD86, CD22, SHP-1, CCR3, CCR4, CXCR1, CXCR2, CXCR3, BLYS, BCMA, OX40L, NKG2A, NKG2C, CD94, IKKA, and associations of the polymorphisms with the diseases were examined. Already known polymorphisms of HLA-DRB1, TNF, FCGR2A, FCGR3A, FCGR3B were genotyped in parallel. A number of new polymorphisms were detected. Significant association with SLE was detected in TNFR2-196R, both of FCGR2B-232T and FCGR3A-176F, CD19 GT repeat polymorphism in 3 untranslated region, for the first time. In addition, HLA-DRB1 *0405 and TNFα-1031C, -863A, -857C haplotype were both found to be associated with Crohn's disease. Furthermore, some alleles were suggested to be associated with disease in combination with alleles of other genes and also some polymorphisms were shown to have functional changes.
The second approach was the expression profiling. Using differential display, 19 gene fragments were found to be preferentially expressed in RA synovia as compared with osteoarthritis, among which Id family genes were considered to be particularly relevant to the pathogenesis of RA. Immunohistochemical staining indicated the localization of Id proteins in endothlial cells, suggesting its role in angiogenesis. In Crohn's disease, genes of particular interest in terms of functions, such as FLIP and TNIK, were found to be upregulated in the inflammatory tissues.
Collectively, both approaches provide a number of important clues to elucidate the genetic background of RA, SLE and Crohn's disease.