| Project/Area Number |
13204059
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
|
| Allocation Type | Single-year Grants |
|---|
| Review Section |
Biological Sciences
|
|---|
| Research Institution | Kobe University |
|---|
Principal Investigator |
SHIOZAWA Shunichi Kobe University, School of Medicine, Professor, 医学部, 教授 (40154166)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Hitoshi Kobe University, School of Medicine, Professor, 医学部, 教授 (30107958)
MIURA Yasushi Kobe University, School of Medicine, Associate Professor, 医学部, 助教授 (60346244)
HASHIRAMOTO Akira Kobe University, School of Medicine, Associate Professor, 医学部, 助教授 (80346246)
KOMAI Koichiro Kobe University, School of Medicine, Assistant Lecturer, 医学部, 助手 (40304117)
塚本 康夫 神戸大学, 学術情報基盤センター, 教授 (30031149)
|
|---|
| Project Period (FY) |
2000 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥52,600,000 (Direct Cost: ¥52,600,000)
Fiscal Year 2004: ¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2003: ¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2002: ¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2001: ¥15,000,000 (Direct Cost: ¥15,000,000)
|
|---|
| Keywords | rheumatoid arthritis (RA) / death receptor 3 (DR3) / disease gene / 遺伝学 / 遺伝子 / 免疫学 / テクノバイオロジー / 内科 / 関節リウマチ / rheumatoid arthritis / 疾患遺伝子 / disease gene / 遺伝素因 / genetic predisposition / DR3,death receptor 3 / 関節破壊 / DR3 / Ang-1 / Dbl / 遺伝解析 / 慢性関節リウマチ |
|---|
| Research Abstract |
BACKGROUND
while the defect in apoptosis causes characteristic systemic autoimmunity in mice, the contribution of apoptosis to human systemic autoimmunity is unclear.
The present study was designed to elucidate the contribution of death receptor 3 (DR3) gene, a member of apoptosis-inducing TNF receptor gene family including Fas, to the pathogenesis of RA.
METHODS
Mutation was identified by sequencing death receptor 3(DR3) genome and assessed in relation to gene expression, molecular assembly, apoptosis induction and the prevalence of RA in 2,480 patients with RA and 1,270 healthy controls in Japan and Korea.
RESULTS
We identified a variant of DR3 gene, a family of apoptosis-inducing Fas gene, containing 4 single nucleotide polymorphisms (SNPs) and one locus of a 14 nucleotide deletion within exon 5 and intron 5 in patients with rheumatoid arthritis (RA), in which g.2590 A>T mutation resulted in insertion of a portion of intron 5 into the coding sequence to generate premature stop codon. Truncated product DR3 molecule lacking death domain assembled with authentic DR3 to inhibit ligand-induced apoptosis in the lymphocytes of patients with mutation. The variant existed in 3.19% of patients with RA among Japanese oriental genealogy with odds ratio 13.9 (p=1.2x10^<-10>).
CONCLUSIONS
Variant DR3 of relatively low frequency generates truncated DR3 molecule lacking death domain, which assembled with authentic DR3 molecule to inhibit apoptosis and predisposes to RA.
|
