2004 Fiscal Year Final Research Report Summary
Identification of autoimmune thyroid disease susceptibility genes
| Project/Area Number |
13204066
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | International Medical Center of Japan (2002-2004)
Kyushu University (2001) |
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Principal Investigator |
HARADA Haruhito International Medical Center of Japan, Research Institute, Division Chief, 臨床病理研究部, 室長 (00271429)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRASAWA Senji International Medical Center of Japan, Research Institute, Director, 臨床病理研究部, 部長 (10253535)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Autoimmune thyroid disease (AITD) / Disease susceptibility genes / Microsatellite markers / SNPs / ZFAT / association study / B cell / Antisense RNA |
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| Research Abstract |
1. Our genome-wide analysis using 123 Japanese sib-pairs affected with AITD identified 19 regions on 14 chromosomes where the multipoint maximum LOD score (MLS) is >1. 5q31-q33 and 8q23-q24 regions yielded suggestive evidence for linkage to AITD (MLS>3).
2. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to AITD: We identified a novel zinc-finger gene, ZFAT (zinc-finger gene in AITD susceptibility region), as a susceptibility gene in 8q23-q24 through an association analysis using the probands in the previous linkage analysis and a subsequent association analysis of the samples from a total of 515 affected individuals and 526 controls. The T allele of Ex9b-SNP10 located in the intron 9 of ZFAT, is associated with increased risk for AITD (dominant model: OR = 1.7, P = 0.000091). The Ex9b-SNP10 falls into the 3'-UTR of truncated-ZFAT (TR-ZFAT) and the promoter region of the small antisense transcript of ZFAT (SAS-ZFAT). In peripheral blood lymphocytes, SAS- ZFAT is exclusively expressed in CD 19+ B cells and expression levels of SAS-ZFAT and TR-ZFAT seemed to correlate with the Ex9b-SNP1O-T allele, inversely and positively, respectively. The results from our functional analyses on the Ex9b-SNP10 suggested that the SNP plays a critical role in B cell function by affecting the expression level of TR-ZFAT through regulating SAS-ZFAT expression.
3. 3'UTR SNPs of the CTLA4 gene, encoding a negative regulator of the T-lymphocyte immune response, were reported to be associated with AITD in the Caucasians. We confirmed that one of the CTLA4 SNPs is associated with Graves' disease and AITD in the Japanese.
4. We found associations between a SNP in the promoter region of FCRL3 (-169C/T) and susceptibility to AITD and SLE. This polymorphism alters the binding affinity of NFkappaB and regulates FCRL3 expression.
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