SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease.
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.
Shirasawa
Senji
S
Department of Pathology, Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan.
Harada
Haruhito
H
Furugaki
Koichi
K
Akamizu
Takashi
T
Ishikawa
Naofumi
N
Ito
Kunihiko
K
Ito
Koichi
K
Tamai
Hajime
H
Kuma
Kanji
K
Kubota
Sumihisa
S
Hiratani
Hitomi
H
Tsuchiya
Tomoko
T
Baba
Iwai
I
Ishikawa
Mayuko
M
Tanaka
Masao
M
Sakai
Kenji
K
Aoki
Masayuki
M
Yamamoto
Ken
K
Sasazuki
Takehiko
T
D001402:B-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D016373:DNA, Antisense / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013967:Thyroiditis, Autoimmune / Q000175:diagnosis / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics*
D016373:DNA, Antisense; D004268:DNA-Binding Proteins