Abstract 295: Genetic Variation at the PCAF Locus Involved in Epigenetic Control Associates with Clinical Endpoints in Two Large Prospective Studies
Epigenetic processes modulate gene expression patterns without modifying the actual DNA sequence. A major influence on this gene expression is attributed to histone acetyltransferases (HATs) which modify chromatin structure to allow gene transcription. P300/CBP associated factor (PCAF) is a transcriptional co-activator with intrinsic HAT-activity. Besides its role in inflammatory gene activation, PCAF is known to directly acetylate tumor-suppressor proteins. It is unknown if frequently occurring variants in genes encoding HATs can influence susceptibility to, or mortality due to, major human diseases, such as cancer and cardiovascular disease, diseases in which inflammation and proliferation are known to play a dominant role. Therefore, we investigated the impact of two polymorphisms in the PCAF promoter on all-cause mortality in a large population of elderly patients at risk for vascular disease (the PROSPER-study, n=5804) and on clinical restenosis after a percutaneous coronary intervention (PCI) for stable angina pectoris (the GENDER-study, n=3104). These endpoints are both determined by inflammation and proliferation. We demonstrate that the -2481C allele in the PCAF gene, which is involved in epigenetic control of gene expression, is associated with a significant survival advantage in the PROSPER-study, while this allele also protects against clinical restenosis after PCI in the GENDER-study (figure 1⇓). We conclude that its effect on these endpoints may be due to the well-known involvement of PCAF in inflammatory and proliferative processes, probably by epigenetic mechanisms.