LINCing genotype and phenotype at the 4q27 coronary artery disease risk locus

Background: Genome-wide association studies identified hundreds of genomic variants associated with coronary artery disease (CAD) and myocardial infarction (MI). One such variant, rs7678555, is located in a gene desert at the chromosome 4q27 locus, which also harbors the PDE5A and MAD2L1 genes. Here, we sought to identify the molecular mechanism linking genotype and phenotype.
 
Methods and Results: We found that the rs7678555 risk allele is associated with increased PDE5A but not altered MAD2L1 expression, and reporter gene assays confirmed a regulatory function of the variant sequence. In human vascular smooth muscle cells (VSMCs) of different individuals, PDE5A expression positively correlated with the expression of LINC02502, a long non-coding (lnc) RNA which is under baseline and proatherosclerotic conditions located in the cytosol in vitro. Using RNA interference and ectopic overexpression, we found that LINC02502 regulates the expression of PDE5A, the gene encoding phosphodiesterase 5A. Mechanistically, this regulation is mediated by the transcription factor REST. As indicated by in silico analyses and RNA-immunoprecipitation experiments, LINC02502 binds REST, potentially preventing its translocation from the cytosol to the nucleus and thereby reducing its repressing effect on PDE5A expression. In addition, LINC02502 promotes proatherosclerotic VSMC phenotypes such as proliferation, migration, and expression of inflammatory transcripts.
 
Conclusion: We identified a mechanism linking rs7678555 genotype and CAD risk involving a lncRNA that was not studied before, i.e., LINC02502. Our data explain how the genetic variant at the chromosome 4q27 locus regulates the expression of PDE5A, which itself represents an established CAD risk gene. Furthermore, our data strengthen the importance of the non-coding genome in complex diseases and point to a novel treatment strategy in CAD and MI.