Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 2221-2231 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 13 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - Oct 1 2004 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Genetics(clinical)
Cite this
SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. / Shirasawa, Senji; Harada, Haruhito; Furugaki, Koichi; Akamizu, Takashi; Ishikawa, Naofumi; Ito, Kunihiko; Ito, Koichi; Tamai, Hajime; Kuma, Kanji; Kubota, Sumihisa; Hiratani, Hitomi; Tsuchiya, Tomoko; Baba, Iwai; Ishikawa, Mayuko; Tanaka, Masao; Sakai, Kenji; Aoki, Masayuki; Yamamoto, Ken; Sasazuki, Takehiko.
In: Human Molecular Genetics, Vol. 13, No. 19, 01.10.2004, p. 2221-2231.Research output: Contribution to journal › Article
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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
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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UR - http://www.scopus.com/inward/citedby.url?scp=5444230036&partnerID=8YFLogxK
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 -