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.
Department of Pathology, Research Institute, International Medical Center of Japan, Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan.
Senji
S
Shirasawa
Haruhito
H
Harada
Koichi
K
Furugaki
Takashi
T
Akamizu
Naofumi
N
Ishikawa
Kunihiko
K
Ito
Koichi
K
Ito
Hajime
H
Tamai
Kanji
K
Kuma
Sumihisa
S
Kubota
Hitomi
H
Hiratani
Tomoko
T
Tsuchiya
Iwai
I
Baba
Mayuko
M
Ishikawa
Masao
M
Tanaka
Kenji
K
Sakai
Masayuki
M
Aoki
Ken
K
Yamamoto
Takehiko
T
Sasazuki
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