Abstract
BackgroundGenome-wide association studies (GWAS) have identified a variant (rs9349379) at the phosphatase and actin regulator 1 (PHACTR1) locus that is associated with coronary artery disease (CAD). The same variant is also an expression quantitative trait locus (eQTL) for PHACTR1 in human coronary arteries (hCA). Here, we sought to characterize PHACTR1 splicing pattern in atherosclerosis-relevant human cells. We also explored how rs9349379 modulates the expression of the different PHACTR1 splicing isoforms.MethodsWe combined rapid amplification of cDNA ends (RACE) with next-generation long-read DNA sequencing to discover all PHACTR1 transcripts in many human tissues and cell types. We measured PHACTR1 transcripts by qPCR to identify transcript-specific eQTLs.ResultsWe confirmed a brain-specific long transcript, a short transcript expressed in monocytes and four intermediate transcripts that are different due to alternative splicing of two in-frame exons. In contrast to a previous report, we confirmed that the PHACTR1 protein is present in vascular smooth muscle cells. In 158 hCA from our collection and the GTEx dataset, rs9349379 was only associated with the expression levels of the intermediate PHACTR1 transcripts.ConclusionsOur comprehensive transcriptomic profiling of PHACTR1 indicates that this gene encodes six main transcripts. Five of them are expressed in hCA, where atherosclerotic plaques develop. In this tissue, genotypes at rs9349379 are associated with the expression of the intermediate transcripts, but not the immune-specific short transcript. This result suggests that rs9349379 may in part influence CAD by modulating the expression of intermediate PHACTR1 transcripts in endothelial or vascular smooth muscle cells found in hCA.
Highlights
Genome-wide association studies (GWAS) have identified a variant at the phosphatase and actin regulator 1 (PHACTR1) locus that is associated with coronary artery disease (CAD)
We did identify a large number of PHACTR1 transcripts due to alternative splicing of non-coding 5′ and 3′ untranslated exons (Additional file 3), our transcriptomic profiling indicates that PHACTR1 can give rise to six main different transcripts that would encode six proteins based on their coding sequences (Fig. 1and Additional file 4)
CAD-associated rs9349379 is an expression quantitative trait locus (eQTL) for PHACTR1 intermediate transcripts A Using primers that capture the long and intermediate PHACTR1 transcripts, we previously showed that genotypes at rs9349379 are associated with PHACTR1 expression levels in human coronary arteries (hCA) [5]
Summary
Genome-wide association studies (GWAS) have identified a variant (rs9349379) at the phosphatase and actin regulator 1 (PHACTR1) locus that is associated with coronary artery disease (CAD). Genome-wide association studies (GWAS) have identified a robust association between coronary artery disease (CAD) and the PHACTR1 locus on chromosome 6p24 [1]. We fine-mapped the CAD association to the candidate causal variant rs9349379 located in an intron of PHACTR1 [5] This SNP disrupts a MEF2 binding site and is an expression quantitative trait locus (eQTL) for PHACTR1 in human coronary arteries (hCA) [5]. Over-expression experiments have implicated PHACTR1 in apoptosis [9], angiogenesis [10], cellular matrix remodelling [11], and cell motility [8] These processes are important for atherogenesis and CAD, the precise role(s) that PHACTR1 plays at the site of atherosclerotic lesions in coronary arteries is unknown
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