| Project/Area Number |
12307056
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Human genetics
|
|---|
| Research Institution | RESEARCH INSTITUTE, INTERNATIONAL MEDICAL CENTER OF JAPAN (2001-2003)
Kyushu University (2000) |
|---|
Principal Investigator |
SHIRASAWA Senji RESEARCH INSTITUTE, INTERNATIONAL MEDICAL CENTER OF JAPAN, DEPARTMENT OF PATHOLOGY, DIRECTOR, 部長 (10253535)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SASAZUKI Takehiko RESEARCH INSTITUTE, INTERNATIONAL MEDICAL CENTER OF JAPAN, DIRECTOR-GENERAL, 所長 (50014121)
HARADA Haruhito RESEARCH INSTITUTE, INTERNATIONAL MEDICAL CENTER OF JAPAN, DEPARTMENT OF PATHOLOGY, SECTION CHIEF, 室長 (00271429)
YAMAMOTO Ken KYUSYU UNIVERSITY, MEDICAL INSTITUTION OF BIOREGULATION, ASSISTANT PROFESSOR, 生体防御医学研究所, 助教授 (60274528)
|
|---|
| Project Period (FY) |
2000 – 2003
|
| Project Status |
Completed (Fiscal Year 2003)
|
| Budget Amount *help |
¥37,730,000 (Direct Cost: ¥31,700,000、Indirect Cost: ¥6,030,000)
Fiscal Year 2003: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2002: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2001: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2000: ¥11,600,000 (Direct Cost: ¥11,600,000)
|
|---|
| Keywords | AITD / susceptibility gene / microsatellite marker / SNP / affected sib-pairs / linkage / association / antisense RNA / ZFAT / B細胞 / Graves病 / 橋本病 / 罹患同胞対法 / SNP / 自己免疫疾患 / 甲状腺 |
|---|
| Research Abstract |
Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is caused by immune response to the thyroid gland and is a complex disease with both genetic and environmental factors. A genome-wide linkage analysis using the affected sib-pairs with AITD was done, indicating that chromosome 5q31-q33 and 8q23-q24 were candidate AITD susceptibility regions. Association analysis using microsatellite markers and SNPs in 8q23-q24 and linkage disequilibrium analysis narrowed the susceptibility region up to 60 kb-length. We have identified a novel zinc-finger gene in AITD susceptibility region, designated ZFAT, as one of the susceptibility genes for AITD, which encodes a protein of 1,253 amino acids with 18-repeats of zinc-finger domains. The T allele of the EX9b-SNP10, located in the intron 9 of ZFAT, is associated with increased risk for AITD (dominant model : odds ratio=1.7, P=0.000091). The Ex9b-SNP10 falls into the 3'UTR of truncated (TR)-ZFAT and the promoter region of the small antisense transcript (SAS)-ZFAT. SAS-ZFAT is exclusively expressed in B cells in peripheral blood lymphocytes, and expression levels of SAS-ZFAT and TR-ZFAT correlated with the Ex9b-SNP10-T, inversely and positively, respectively. In vitro analysis revealed that the Ex9b-SNP10 is critically involved in the regulation of SAS-ZFAT expression and this expression results in a decreased expression of TR-ZFAT. All these results, together, suggested that the Ex9b-SNP10-associated ZFAT-allele might play a critical role in B cell function by affecting the expression level of TR-ZFAT through regulating SAS-ZFAT expression.
|
