Abstract 3141: Is Gene Expression at Chromosome 9p21 Associated with Coronary Artery Disease Susceptibility?
Objective: Genome-wide association studies have revealed a novel locus of coronary artery disease (CAD) susceptibility on human chromosome (Chr) 9p21. No known genes reside within the identified haplotype block. In order to unravel potential molecular mechanisms underlying this locus, we determined mRNA expression of all annotated genes in proximity of the core Chr 9 haplotype block (+/− 350 kb) and investigated whether differential mRNA expression of these genes was associated with CAD susceptibility.
Methods and Results: Bioinformatic analysis revealed regulatory elements, potentially affecting mRNA expression of genes in the Chr 9p21 region. Since blood derived mononuclear cells (PBMC) are a major source of cells within atherosclerotic lesions, these cells were isolated from 760 participants of the Leipzig Heart study, a cohort of patients with varying severity of CAD. The Chr 9p21 locus was replicated in this cohort by genotyping 4 tagging SNPs rs2383206, rs2383297, rs10757274, rs10757278 (P = 8.4 × 10−5). We determined mRNA expression of all annotated genes in PBMC using transcript-specific quantitative RT-PCR. Whereas the cyclin-dependent kinase CDKN2A with its transcripts p14(ARF) and p16(INK4) and CDKN2B were only weakly expressed (39 copies/107 copies beta-actin (107 BA), 44 copies/107 BA, and 179 copies/107 BA, respectively), we observed higher expression of the two MTAP transcripts (6183 copies/107 BA and 6007 copies/107 BA), C9orf53 (961 copies/107 BA) and DMRTA1 (623 copies/107 BA). The expression of these transcripts was neither associated with the degree of CAD nor with the genotype at Chr 9p21. This is of interest since to date, in particular CDKN2A and CDKN2B have been considered as potential candidates of CAD susceptibilty due to their crucial role in cell cycle regulation.
Conclusions: This is to our knowledge the first study investigating gene expression and association with CAD susceptibility at the Chr 9p21 locus. Analysis of mRNA expression in PBMCs from 760 participants of the Leipzig Heart Study revealed no association of genes in the proximity of the Chr 9p21 locus with severity of CAD. These data suggest that other molecular mechanisms might be responsible for the Chr 9p21 association with CAD.