Splice variants of lncRNA RNA ANRIL exert opposing effects on endothelial cell activities associated with coronary artery disease.

Each gene typically has multiple alternatively spliced transcripts. Different transcripts are assumed to play a similar biological role; however, some transcripts may simply lose their function due to loss of important functional domains. Here, we show that two different transcripts of lncRNA gene ANRIL associated with coronary artery disease (CAD) play antagonizing roles against each other. We previously reported that DQ485454, the short transcript, is downregulated in coronary arteries from CAD patients, and reduces monocyte adhesion to endothelial cells (ECs) and transendothelial monocyte migration (TEM). Interestingly, the longest transcript NR_003529 is significantly upregulated in coronary arteries from CAD patients. Overexpression of ANRIL transcript NR_003529 increases monocyte adhesion to ECs and TEM, whereas knockdown of NR_003529 expression reduces monocyte adhesion to ECs and TEM. Much more dramatic effects were observed for the combination of overexpression of NR_003529 and knockdown of DQ485454 or the combination of knockdown of NR_003529 and overexpression of DQ485454. The antagonizing effects of ANRIL transcripts NR_003529 and DQ485454 were associated with their opposite effects on expression of downstream target genes EZR, CXCL11 or TMEM106B. Our results demonstrate that different transcripts of lncRNA can exert antagonizing effects on biological functions, thereby providing important insights into the biology of lncRNA. The data further support the hypothesis that ANRIL is the causative gene at the 9p21 CAD susceptibility locus.

Genomic variant in CAV1 increases susceptibility to coronary artery disease and myocardial infarction.

BACKGROUND: The CAV1 gene encodes caveolin-1 expressed in cell types relevant to atherosclerosis. Cav-1-null mice showed a protective effect on atherosclerosis under the ApoE(-/-) background. However, it is unknown whether CAV1 is linked to CAD and MI in humans. In this study we analyzed a tagSNP for CAV1 in intron 2, rs3807989, for potential association with CAD. METHODS AND RESULTS: We performed case-control association studies in three independent Chinese Han populations from GeneID, including 1249 CAD cases and 841 controls in Population I, 1260 cases and 833 controls in Population II and 790 cases and 1212 controls in Population III (a total of 3299 cases and 2886 controls). We identified significant association between rs3807989 and CAD in three independent populations and in the combined population (Padj = 2.18 × 10(-5), OR = 1.19 for minor allele A). We also detected significant association between rs3807989 and MI (Padj = 5.43 × 10(-5), OR = 1.23 for allele A). Allele A of SNP rs3807989 was also associated with a decreased level of LDL cholesterol. Although rs3807989 is a tagSNP for both CAV1 and nearby CAV2, allele A of SNP rs3807989 was associated with an increased expression level of CAV1 (both mRNA and protein), but not CAV2. CONCLUSIONS: The data in this study demonstrated that rs3807989 at the CAV1/CAV2 locus was associated with significant risk of CAD and MI by increasing expression of CAV1 (but not CAV2). Thus, CAV1 becomes a strong candidate susceptibility gene for CAD/MI in humans.