SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease

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 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.

ZFAT is a critical molecule for cell survival in mouse embryonic fibroblasts

“…It affects 2-5% of the general population [1]. Through linkage and association analyses on a large group of Japanese AITD patients [2,3], we identified ZFAT (the zincfinger gene in the AITD susceptibility region) as a susceptibility gene for AITD [3]. The human ZFAT gene encodes a 1,243-amino acid residue protein containing one AT-hook and 18 C2H2 zinc-finger domains.…”

ZFAT is essential for endothelial cell assembly and the branch point formation of capillary-like structures in an angiogenesis model

“…The human ZFAT gene was originally identified as a susceptibility gene for autoimmune thyroid disease [1]. ZFAT encodes a transcriptional regulator containing one AT-hook and 18 C 2 H 2 -type zinc-finger domains, and it is highly conserved across species from fish to human [2].…”

Evaluation of genetic loci influencing adult height in the Japanese population

“…Our study could replicate significant association at a new locus, ZFAT, which has not been reported in Europeans but is likely to exert some genetic impacts on height in East Asians (Japanese and Koreans) (Table 1 and Supplementary Table 5). Apart from the genetic susceptibility to autoimmune thyroiditis reported in the Japanese, 15 little is known about the function of ZFAT. Further investigation of this locus is warranted to provide novel insights into human growth.…”