Abstract
BackgroundThe ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression.ResultsWe genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p = 4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p = 7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies.ConclusionsZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-014-0136-1) contains supplementary material, which is available to authorized users.
Highlights
The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues
Expression ratios at individual transcribed markers showed inter-individual variation, the range of the ratio of the minor:major alleles was 0.71:1– 1.65:1 for both transcripts taken together and 0.39:1– 1.48:1 for transcript A alone, indicating that ZFHX3 expression is regulated by factors which differ between individuals and that there was greater interindividual variability in the allelic expression ratio (AER) of transcript A
We have shown that multiple Single nucleotide polymorphism (SNP) in the ZFHX3 region are significantly associated with ZFHX3 expression in whole blood in a transcript specific manner
Summary
The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. Genome-wide association studies (GWAS) have identified associations between single-nucleotide polymorphisms (SNPs) in this region and atrial fibrillation (AF) [1,2,3], Kawasaki disease [4] and cardioembolic stroke [2,5]. ZFHX3, formerly known as ATFB1, is the only protein-coding gene within 500 kb of the GWAS hit SNPs. ZFHX3 codes for a transcription factor (TF) which is widely expressed and is reported in all 16 tissues covered by the Body Map 2.0 project [6]. Absence of ZFHX3 expression and mutations near the ATP binding domain are associated with an increase in malignant activity in hepatocellular, gastric, breast and prostate carcinoma [8,9,10,11]
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