TY - JOUR
T1 - SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease
AU - Shirasawa, Senji
AU - Harada, Haruhito
AU - Furugaki, Koichi
AU - Akamizu, Takashi
AU - Ishikawa, Naofumi
AU - Ito, Kunihiko
AU - Ito, Koichi
AU - Tamai, Hajime
AU - Kuma, Kanji
AU - Kubota, Sumihisa
AU - Hiratani, Hitomi
AU - Tsuchiya, Tomoko
AU - Baba, Iwai
AU - Ishikawa, Mayuko
AU - Tanaka, Masao
AU - Sakai, Kenji
AU - Aoki, Masayuki
AU - Yamamoto, Ken
AU - Sasazuki, Takehiko
N1 - Funding Information:
We thank all patients for participating in this study, Dr Sumio Sugano for helpful discussion, S. Ohkubo for preparation of the manuscript and T. Tokuyasu, Y. Hagishima, A. Murakami, E. Yachi, J. Nakai, S. Oishi, T. Akinaga, H. Yamaguchi and K. Fukuyama for technical assistance. This work was supported by a Grant-in Aid for Scientific Research on Priority Areas ‘Medical Genome Science’ from the Ministry of Education, Science, Technology, Sports and Culture, Japan, and a Grant-in Aid for Scientific Research (A) from the Japan Society for the Promotion of the Science, a Research Grant on Human Genome and Gene Therapy from the Ministry of Health, Labour and Welfare, Japan and the Japan Science and Technology Corporation (CREST).
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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 pro-bands 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.
AB - 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 pro-bands 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.
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U2 - 10.1093/hmg/ddh245
DO - 10.1093/hmg/ddh245
M3 - Article
C2 - 15294872
AN - SCOPUS:5444230036
VL - 13
SP - 2221
EP - 2231
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 19
ER -