Abstract
Objectives Because post-transcriptional mechanisms modulate levels of p16 (encoded by CDKN2A) and p15 (encoded by CDKN2B), we tested whether interferon-gamma regulates the expression of these proteins and the effect of the 9p21 genotype.
Background The mechanism whereby the common variant at chromosome 9p21.3 confers risk for coronary artery disease (CAD) remains uncertain. A recent report proposed that 9p21.3 confers differential activation of adjacent genes in response to interferon-gamma, and reported that mRNA levels of CDKN2B are reduced in response to interferon-gamma.
Methods Human umbilical vein endothelial cells (HUVECs), aortic smooth muscle cells, HeLa cells, HEK293 cells, and 16 human lymphoblastoid cell lines, all genotyped for the 9p21.3 locus, were treated with interferon-gamma and analyzed by immunoblot.
Results In all cells tested-except HUVECs where expression was not modulated by interferon-gamma-regardless of 9p21.3 genotype, interferon-gamma increased the expression of p16 and p15. Northern blot analysis confirmed that interferon-gamma has little effect on mRNA levels of CDKN2A and CDKN2B.
Conclusions The 9p21.3 risk genotype does not affect the activation of cyclin-dependent kinase inhibitors p15 and p16 by interferon-gamma. Thus, another mechanism is likely to account for the CAD risk associated with this locus. (J Am Coll Cardiol 2013; 61: 143-7) (C) 2013 by the American College of Cardiology Foundation