Stenvinkel Peter, Ekström Tomas J
Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
Contrib Nephrol. 2008;161:55-62. doi: 10.1159/000129754.
Epigenetics, which is the study of changes in gene expression that occur without changes in DNA sequence, is a novel discipline that has languished in the shadow of its genomic big brother. So far, studies of the epigenome have attracted little interest in nephrology. Chronic kidney disease is an example of complex disease in which the phenotype arises from a combination of environmental and heritable factors. Evidence suggests that the contribution made by the environment may be mediated via modifications of the epigenome. In the uremic milieu, several features such as inflammation, dyslipidemia, hyperhomocysteinema, oxidative stress as well as vitamin and nutritional deficiencies may affect aberrant global DNA methylation. However, as hyperhomocysteinemia seems to promote global DNA hypomethylation and persistent inflammation DNA hypermethylation, the effects of the uremic milieu on aberrant global DNA methylation may be complex and context-sensitive. It should be emphasized that in analogy to the unspecific nature of fever, aberrant global DNA methylation is only a sign of a generalized epigenetic dysregulation. Thus, to provide better understanding of the effects of aberrant DNA methylation on the uremic phenotype, further studies evaluating site-specific information on methylation in various candidate genes are needed. The science of epigenetics may not only uncover etiologic and pathogenic mechanisms in uremia, but may also be of help to develop novel treatment strategies targeting the unacceptable high death risk in cardiovascular complications in this patient population.
表观遗传学是研究在DNA序列不变的情况下发生的基因表达变化的学科，它是一门长期处于其基因组“老大哥”阴影下的新兴学科。到目前为止，表观基因组的研究在肾脏病学领域几乎没有引起关注。慢性肾脏病是一种复杂疾病，其表型由环境因素和遗传因素共同作用产生。有证据表明，环境因素的作用可能是通过表观基因组的修饰来介导的。在尿毒症环境中，炎症、血脂异常、高同型半胱氨酸血症、氧化应激以及维生素和营养缺乏等多种因素可能会影响异常的全基因组DNA甲基化。然而，由于高同型半胱氨酸血症似乎会促进全基因组DNA低甲基化，而持续性炎症会导致DNA高甲基化，所以尿毒症环境对异常全基因组DNA甲基化的影响可能是复杂的且具有背景依赖性。应该强调的是，类似于发热的非特异性本质，异常的全基因组DNA甲基化只是一种全身性表观遗传失调的标志。因此，为了更好地理解异常DNA甲基化对尿毒症表型的影响，需要进一步开展研究，评估各种候选基因中甲基化的位点特异性信息。表观遗传学不仅可能揭示尿毒症的病因和发病机制，还可能有助于制定针对该患者群体心血管并发症中不可接受的高死亡风险的新型治疗策略。
