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
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
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DOI：
10.1136/hrt.2010.199927
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发表时间：
2011-01-01
期刊：
影响因子：
5.7
通讯作者：
Jukema, J. Wouter
中科院分区：
文献类型：
--
作者：
Pons, Douwe;Trompet, Stella;Jukema, J. Wouter
目的本研究旨在探讨基因编码P300/CBP相关因子（PCAF），赖氨酸乙酰转移酶（KAT），对冠心病（CHD）和mortarity.Methods和结果的基因启动子的遗传变异的平衡影响的关联PCAF基因与CHD，再狭窄和死亡率进行了研究，在三个大的队列。将结果结合起来检查对CHD死亡率和再狭窄风险的总体影响。与PCAF启动子中纯合的-2481G等位基因相比，观察到纯合的-2481C PCAF启动子等位基因的CHD死亡风险显著降低。三项研究的CHD死亡风险降低率为21%（15-26%; p=8.13X10（-4））。在老年患者（> 58岁）中，效果更强。此外，该PCAF等位基因与全因死亡率显著相关（p=0.001）。功能分析表明，核因子在体外与包含-2481 G/C多态性的寡核苷酸相互作用，这种相互作用可能受到PCAF启动子中的这种多态性的影响。此外，调制PCAF基因的表达是可检测的袖口放置在反应性stenosis.Conclusion的动物模型后，我们表明，在三个大型前瞻性研究中，-2481C等位基因的PCAF启动子与老年患者的生存优势显着。我们的观察促进了表观遗传过程受遗传控制的概念，并且除了环境之外，编码KAT的基因的变异也可能决定CHD结局和死亡率的易感性。
Aims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality.Methods and results 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. 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=8.13X10(-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.Conclusion We showed in three large prospective studies that the -2481C allele in the PCAF promoter is associated with a significant survival advantage in elderly patients. Our observations promote the concept that epigenetic processes are under genetic control and that, other than environment, variation in genes encoding KATs may also determine susceptibility to CHD outcomes and mortality.