11 A Statistical Framework for Mediation in Environmental Epigenetics

摘要

"Epigenetics" refers to factors affecting the expression of genes without changes in the underlying DNA sequence. The best studied is DNA methylation, but other changes include various posttranslational histone modifications, regulation by noncoding microRNAs, and so forth. These mechanisms play a central role in X-chromosome inactivation and genomic imprinting. Our focus is initially on epigenetic changes that can be transmitted mitotically in somatic cells (later we will consider meiotic transmission), potentially providing a mechanism by which environmental exposures can affect gene expression and hence disease risk or other traits. Indeed, it has been demonstrated that MZ twins (who are genetically identical) have similar DNA methylation and histone acetylation patterns--both globally and at specific loci--early in life, but acquire remarkably large differences as they age, possibly in response to different exposure histories but also possibly just due to random drift. However, heritability of DNA methylation may depend on the locus in question. Recent work evaluating heritability of DNA methylation in AXL, a receptor tyrosine kinase relevant in cancer and immune function, found a low level of heritability in twins as young as nine years of age. Ever since Barker proposed a fetal basis of adult disease (the "Barker hypothesis"), a broad range of epidemiologic research has implicated various environmental exposures during prenatal and early postnatal development as influencing the risk of adult cardiovascular disease, obesity, type 2 diabetes, and other chronic diseases. More recently, de Boo and Harding and Waterland and Jirtle have discussed the evidence that epigenetics may provide the mechanistic basis for these associations.