The mechanisms of Chr.9p21.3 risk locus in coronary artery disease: where are we today?

Despite the advancements and release of new therapeutics in the past few years, cardiovascular diseases (CVDs) have remained the number one cause of death worldwide. Genetic variation of a 9p21.3 genomic locus has been identified as the most significant and robust genetic CVD risk marker on the population level, with the strongest association with coronary artery disease (CAD) and other diseases, including diabetes and cancer. Several mechanisms of 9p21.3 in CVDs have been proposed, but their effects on CVDs have remained elusive. Moreover, most of the single nucleotide polymorphisms (SNPs) associated with CAD are located on a sequence of a long noncoding RNA (lncRNA) called ANRIL. ANRIL has several linear and circular splicing isoforms, which seem to have different effects and implications for CVDs. The mechanisms of the 9p21.3 locus and the interplay of its coding and noncoding transcripts in different diseases require further research. Circular RNAs have generally raised interest due to their beneficial features as biomarkers and therapeutic molecules. Here, we review the literature of 9p21.3 from its identification in 2007 and draw the current knowledge on its function, implications in CVDs, and therapeutic potential.