The long non-coding RNA ANRIL is the best replicated genetic risk locus of coronary artery disease (CAD) and periodontitis
(PD), and is independently associated with a variety of other immune-mediated and metabolic disorders and several forms of
cancer. Recent studies showed a correlation of decreased concentrations of proximal ANRIL transcripts with homozygous carriership
of the CAD and PD main risk alleles. To elucidate the relation of these transcripts to disease manifestation, we constructed
a short hairpin RNA in a stable inducible knock-down system of T-Rex 293 HEK cell lines, specifically targeting the proximal
transcripts EU741058 and DQ485454. By genome-wide expression profiling using Affymetrix HG1.0 ST Arrays, we identified the
transcription of ADIPOR1, VAMP3 and C11ORF10 to be correlated with decreased ANRIL expression in a time-dependent manner.
We validated these findings on a transcriptional and translational level in different cell types. Exploration of the identified
genes for the presence of disease associated variants, using Affymetrix 500K genotyping and Illumina custom genotyping arrays,
highlighted a region upstream of VAMP3 within CAMTA1 to be associated with increased risk of CAD [rs10864294 P = 0.015, odds
ratio (OR) = 1.30, 95% confidence interval (CI) = 1.1-1.6, 1471 cases, 2737 controls] and aggressive PD (AgP; P = 0.008, OR
= 1.31, 95% CI = 1.1-1.6, 864 cases, 3664 controls). In silico replication in a meta-analysis of 14 genome-wide association
studies of CAD of the CARDIoGRAM Consortium identified rs2301462, located on the same haplotype block, as associated with
P = 0.001 upon adjustment for sex and age. Our results give evidence that specific isoforms of ANRIL regulate key genes of
glucose and fatty acid metabolism.