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Genetic Variation in PCAF, a Key Mediator in Epigenetics, Is Associated With Reduced Vascular Morbidity and Mortality: Evidence for a New Concept From Three Independent Prospective Studies
Study Questions:
Are PCAF gene variants associated with coronary heart disease (CHD) and mortality?
Methods:
The association of genetic variation in the PCAF-gene with CHD, restenosis, and mortality was investigated in three large cohorts. The results were combined to examine overall effects on CHD mortality and on restenosis risk.
Results:
Compared with the homozygous -2481G allele in the PCAF promoter, a significant reduction in CHD mortality risk with the homozygous -2481C PCAF promoter allele was observed. A combined risk reduction for CHD death for the three studies was 21% (15-26%; p = 8.1 x 10-4). In elderly patients (>58 years), the effects were stronger. Furthermore, this PCAF allele was significantly associated with all-cause mortality (p = 0.001). Functional analysis showed that nuclear factors interact in vitro with the oligonucleotides encompassing the -2481G/C polymorphism, and that this interaction might be influenced by this polymorphism in the PCAF promoter. Moreover, modulation of PCAF gene expression was detectable upon cuff-placement in an animal model of reactive stenosis.
Conclusions:
Based on these three large prospective studies, the -2481C allele in the PCAF promoter is associated with reduced cardiovascular endpoints and a significant survival advantage in elderly patients.
Perspective:
Epigenetics refers to heritable phenotypes not due to changes in nucleotide sequence. For example, PCAF may modify the expression of other genes through lysine acetylation of histones at the site of NFkB-regulated genes. PCAF could thus broadly regulate inflammatory responses. This study examined the association of a promoter polymorphism in PCAF with vascular endpoints. The results support a potential role of this gene in vascular disease, and the restenosis data support its involvement in a cellular proliferative process. However, additional studies are necessary to prove a cause and effect relationship between this polymorphism and vascular outcomes, as well as to determine potential mechanisms responsible for these effects.
Keywords: Oligonucleotides, Coronary Artery Disease, Epigenesis, Genetic, Polymorphism, Genetic, Coronary Disease
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