(Epi)genetic factors in vascular disease
Pons, D.
Citation
Pons, D. (2011, September 22). (Epi)genetic factors in vascular disease.
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Chapter 10
appendix
179 Editorial: The genetics of epigenetics: is there a link with cardiovascular disease
EDITORIAL: THE GENETICS OF EPIGENETICS: IS THERE A LINK WITH CARDIOVASCULAR DISEASE?
Qingzhong Xiao, Shu Ye Heart 2011;97: 96-97
There is evidence indicating that altered epigenetic regulation of gene expression in inflammatory and vascular cells plays a role in the development of atherosclerosis and cardiovascular diseases.1 DNA in the nuclei of eukaryotic cells wraps around histone proteins, forming nucleosomes which are further packaged to form chromosomes, and the combination of DNA, histone and other proteins in chromosomes is referred to as the chromatin. Histones are susceptible to chemical modifications which can alter the chromatin structure, consequently increasing or decreasing the accessibility of DNA elements to transcription factors that regulate gene transcription.
The most extensively studied histone modification is acetylation by the action of histone acetyltransferases.2 P300/CBP associated factor (PCAF) is one of a number of proteins with acetyltransferase activity and can acetylate histones as well as many non-histone proteins that regulate the expression of genes involved in inflammation and cell prolif- eration. 3-6 In this issue of Heart, Pons et al. provide evidence of an association between a single nucleotide polymorphism (SNP) in the PCAF gene promoter and reduced risk of coronary heart disease (CHD) mortality and restenosis.7 The authors studied three population cohorts previously recruited in the PROSPER, WOSCOPS and GENDER studies, the former two being prospective, randomised placebo-controlled pravasatin trails for prevention of cardiovascular events and the latter being a follow-up study of clinical restenosis after percutaneous coronary intervention. An association between the SNP and reduced CHD mortality was detected in PROSPER and a non-significant trend in WOSCOPS, while a relationship between the SNP and reduced risk of clinical restenosis was observed in GENDER. A meta-analysis of the three data sets estimated that individuals who were heterozygous for the low-risk allele had ~20% lower risk of the cardiovascular events (pooled HR of 0.82 (95% CI 0.68 to 0.98)) and individuals who were homozygous for this allele had ~40% lower risk (HR 0.61 (95% CI 0.44 to 0.84)). To provide a possible explanation for the association, the authors show that PCAF expres- sion is increased in a mouse model of mechanical injury-induced neointima formation and provide some evidence suggesting that the SNP associated with reduced risk of cardiovascular events in humans might have an effect on PCAF expression.
A strength of the study of Pons et al. is the replication of the relationship between the genetic variation and cardiovascular traits in three independent cohorts. However, before the PCAF gene variant can be reliably regarded as a genetic factor for CHD,
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further replications of the association will still be required. A handful of accepted CHD-associated genomic loci have recently been identified via genomewide association studies with subsequent confirmation in replication studies.8-11 The PCAF gene does not reside at any of these loci. Nevertheless, since the handful of accepted loci identified so far only account for a small proportion of the heritability of the disease, it is likely that many more CHD-associated loci are still yet to be uncovered, and it is possible that the PCAF locus could be one of them.
The SNP (-2481G/C) found to be associated with the cardiovascular traits in the study of Pons et al. is located in the promoter region of the PCAF gene. The authors provide results from electrophoretic mobility shift assays which suggest that the SNP might affect binding of a nuclear protein (whose identity is unknown) to the PCAF gene promoter, which could potentially have an effect on PCAF transcription. If this is indeed the case, the association between the SNP and cardiovascular events could be due to altered expression of PCAF and consequently changes in the expression of genes regulated by PCAF. Alternatively, the SNP (-2481G/C) may be just a proxy marker for a functional SNP located elsewhere at the PCAF locus due to linkage disequilibrium. If this is the case, because the ‘functional SNP’ has not been identified, it is unknown what functional effect it exerts -i.e., it is unknown whether it affects the level of PCAF expres- sion or its acetyltransferase activity, or something else. Despite a number of unanswered questions, the study of Pons et al. suggests a potential link between cardiovascular events and genetic variation of PCAF whose acetyltransferase activity renders it as having a role in epigenetic regulation. If confirmed, the finding will add to the growing evidence that altered epigenetic regulation of gene expression plays a part in the development of atherosclerosis and cardiovascular diseases.
181 Editorial: The genetics of epigenetics: is there a link with cardiovascular disease
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