PHACTR1 splicing isoforms and eQTLs in atherosclerosis-relevant human cells

Area of Science:

• Genomics
• Molecular Biology
• Cardiovascular Research

Background:

• Genome-wide association studies (GWAS) identified the rs9349379 variant at the PHACTR1 locus associated with coronary artery disease (CAD).
• This variant functions as an expression quantitative trait locus (eQTL) for PHACTR1 in human coronary arteries (hCA).

Purpose of the Study:

• To characterize the PHACTR1 splicing patterns in human cells relevant to atherosclerosis.
• To investigate how the rs9349379 variant modulates the expression of different PHACTR1 splicing isoforms.

Main Methods:

• Discovery of PHACTR1 transcripts using rapid amplification of cDNA ends (RACE) and long-read DNA sequencing.
• Quantification of PHACTR1 transcripts via qPCR to identify transcript-specific eQTLs.

Main Results:

• Identified six main PHACTR1 transcripts, including brain-specific, monocyte-specific, and four intermediate isoforms generated by alternative splicing.
• Confirmed PHACTR1 protein presence in vascular smooth muscle cells.
• The rs9349379 variant was significantly associated with the expression of intermediate PHACTR1 transcripts in hCA.

Conclusions:

• PHACTR1 encodes multiple transcripts, with five expressed in hCA.
• The rs9349379 variant's association with intermediate PHACTR1 transcripts in hCA suggests a mechanism for CAD risk.
• This variant may influence CAD by altering PHACTR1 expression in endothelial or vascular smooth muscle cells within hCA.