Martin Ruairidh I R, Owens W Andrew, Cunnington Michael S, Mayosi Bongani M, Koref Mauro Santibáñez, Keavney Bernard D
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Division of Cardiothoracic Services, The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK.
BMC Genet. 2014 Dec 24;15:136. doi: 10.1186/s12863-014-0136-1.
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. 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.
We 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.
ZFHX3 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.
ZFHX3基因位于16号染色体的16q22.3区域，编码一种在人体组织中广泛表达的转录因子。全基因组研究已经确定该基因内的变异与川崎病和心房颤动之间存在关联。ZFHX3有两个主要转录本，它们利用不同的转录起始位点。我们研究了16q22.3区域的基因变异与ZFHX3表达之间的关联，以确定调控基因表达的变异。
我们对65个单核苷酸多态性进行了基因分型，以标记ZFHX3基因座在两个队列中的遗传变异，一个队列是在英格兰东北部招募的451名英国个体，另一个队列是在南非招募的310名混合血统个体。等位基因表达分析显示，ZFHX3第一个内含子中的变异rs8060701的次要（A）等位基因与两个转录本的等位基因表达共同下降1.16倍相关（p = 4.87e-06）。ZFHX3同工型A第二个外显子中的一个转录变异rs10852515的次要（C）等位基因与ZFHX3 A的等位基因表达独立下降1.36倍相关（p = 7.06e-31），但与ZFHX3的整体表达无关。然而，对ZFHX3总基因表达的分析未能检测到与任何变异的基因型存在关联。两个群体之间连锁不平衡的差异使得该基因座能够精细定位到一个与ZFHX3 A外显子2重叠的7 kb区域。我们没有发现ZFHX3表达与全基因组关联研究确定的任何变异之间存在关联。
ZFHX3转录以转录本特异性的方式由独立的顺式作用转录多态性调控。我们的结果证明了等位基因表达分析和跨种族精细定位在识别转录本特异性顺式作用调控元件方面的作用。
