Human Molecular Genetics Advance Access originally published online on August 4, 2004
Human Molecular Genetics 2004 13(19):2221-2231; doi:10.1093/hmg/ddh245
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Human Molecular Genetics, Vol. 13, No. 19 © Oxford University Press 2004; all rights reserved
SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease
1Department of Pathology, Research Institute, International Medical Center of Japan, Toyama1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan, 2Kyoto University, Kyoto 606-8507, Japan, 3Ito Hospital, Tokyo 150-8308, Japan, 4Kuma Hospital, Kobe 650-0011, Japan, 5Department of Surgery and Oncology and 6Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
Received May 7, 2004; Revised July 6, 2004; Accepted July 20, 2004
Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigens and has a significant genetic component. Antisense RNA transcripts have been implicated in gene regulation. Here we have identified a novel zinc-finger gene, designated ZFAT (zinc-finger gene in AITD susceptibility region), as one of the susceptibility genes in 8q23–q24 through an initial 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 the single-nucleotide polymorphism (SNP), 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-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 CD19+ B cells and expression levels of SAS-ZFAT and TR-ZFAT seemed to correlate with the Ex9b-SNP10-T-associated ZFAT-allele, inversely and positively, respectively. The Ex9b-SNP10 is critically involved in the regulation of SAS-ZFAT expression in vitro and this expression results in a decreased expression of TR-ZFAT. These results suggested that the SNP-associated ZFAT-allele plays a critical role in B cell function by affecting the expression level of TR-ZFAT through regulating SAS-ZFAT expression and that this novel regulatory mechanism of SNPs might be involved in controlling susceptibility or resistance to human disease.
* To whom correspondence should be addressed. Tel: +813 32027181; Fax: +813 32027364; Email: sasazuki{at}nciryo.hosp.go.jp
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