Epigenetics of T2DM
Genome-wide Association Studies (GWAS) have so far identified ~ 70 loci robustly associated to type 2 diabetes and have delivered important lessons on how genetic variation may contribute to causation of the metabolic disturbance. However, despite their growing number, common genetic variants explain only ~ 10% of T2D heritability, a situation often referred to as “missing inheritance”. Thus, to date, up to 90% of T2D inheritance remains unknown. This section deals with the significance of epigenetics for type 2 diabetes.
Epigenetics in the post-GWAS era
As in the case of other complex disorders, several hypotheses are being investigated to explain the missing heritability of T2D (1). These include the following. , Rare variants (minor allele frequency < 0.5%) that are not captured by currently available GWAS platforms; 2, Epistasis (gene-gene interactions) which is presently being analyzed by exploiting GWAS to test all known significant polymorphisms (SNPs) so far identified; 3, Epigenetic modifications, with possible interactions between genetics and epigenetics, as proposed for other complex disorders.
Impact of epigenetics on gene function
Figure 1 Mechanisms of epigenetic regulation. DNA Methylation, histone modifications and miRNA-related gene silencing represent the main mechanisms of epigenetic regulation. a) DNA methylation: it commonly involves clustered cytosine/guanine pairs (CpG) in the promoter region of genes, and is associated to silent genes; b) Histone modifications: different changes occurring at histone proteins (i.e. methylation, Me; acetylation, Ac; and phosphorylation, P) contribute to rendering a DNA region either accessible for transcription or silenced. c) miRNA-related gene silencing: miRNAs bind directly to the 3´-UTR of the target mRNA and regulate either post-transcriptional modifications and control the mechanisms of translational inhibition or destabilize their target mRNAs. (Click to enlarge)Epigenetics refers to modifications that amend the genotype without changing the DNA sequence. Quite commonly, epigenetic changes mediate environmental modulation of gene transcription . Epigenetic processes may involve chemical modifications to DNA, such as methylation, or to DNA-associated proteins, such as histones. These changes commonly affect chromatin state and DNA binding of transcription factors, thereby modify gene transcription.
Thus, epigenetic effects may modulate gene function or turn it on and off, very much like SNPs and other mutations. Epigenetics further refer to microRNAs (miRNAs) that are involved in the regulation of gene expression. Indeed, miRNA dysregulation in type 2 diabetes is receiving increasing interest both from the pathogenetic perspective and because of its potential biomarker significance.
Epigenetics and the familial component of obesity and T2D risk
Lifestyle-related factors, such as the quality of nutrition, the level of physical activity and cigarette smoking have an extraordinary impact on risk of obesity and T2D. All of these factors are potentially capable to cause epigenetic modifications and are often shared within families similar to DNA mutations.
Thus, the hypothesis that environmentally-induced epigenetic effects contribute to the family component of the obesity and T2D risk and account for the missing inheritance of these disorders is being explored in detail .
Whether environmentally-induced epigenetic modifications, once established, can be transgenerationally transmitted hasn’t beed proved yet in humans. However, rodent studies teached that this is a likely possibility as certain DNA methylation changes are stable enough to survive meiosis and be passed along several generations. For instance, in the rat model, the exposure of the male parent to an high-fat dietary regimen programs beta-cell dysfunction in the progeny by modifying the methylation profile of genes responsible for maintaining beta-cell mass . This impressive finding has been further extended by an independent group of investigators who showed that the exposure of female mice to a similar diet causes insulin-resistance in the offspring which persisted in the following two generations . As in the former case, epigenetic mechanisms were involved.
Lifestyle effect on epigenome plasticity: clinical significance
Figure 2 Environment and epigenome. Different environmental determinants may modulate gene function through epigenetic modifications. While some of these might be beneficial for health (i.e. exercise, microbiome and healthy eating habits), others might be harmful (i.e. aging, stress, drugs and bad eating habits) and might promote disease or psychological disorder.The epigenome represents a dynamic interface through which gene function rapidly adapts to changes in the surrounding environment . The investigation of human epigenetic profiles has revealed major differences in obese and lean individuals as well as in T2D and non-diabetic subjects . Several genes responsible for these differences are physiologically involved in metabolic control, but whether their epigenetic modification have a pathogenetic role in development of obesity or T2D has not been conclusively assessed yet.
Importantly however, recent studies demonstrated the feasibility of lifestyle interventions aimed at targetting the plasticity of the epigenome. For example, physical exercise has been shown to induce methylation and parallel transcriptional changes at many genes featuring a potential role in obesity and type 2 diabetes . Similar changes also occur upon bariatric surgery , supporting the concept that the epigenome deserves to be investigated further as an innovative target for pharmacological and lifestyle interventions aimed at prevention and treatment of obesity and T2D.
Epigenotypes as markers of risk of obesity and type 2 diabetes
The hypothesis that specific epigenotypes contribute to the risk of obesity and T2D has been recently demonstrated in prospective studies. Godfrey and co-workers have shown that the epigenetic profile at birth predicts both specific nutritional details during pre-natal life and the adiposity level in infancy . These authors have analyzed the methylation state of the retinoid receptor promoter in two independent cohorts. The retinoid receptor has a major function in controlling adipocyte biology and insulin action and, in both cohorts the methylation level of specific regions of its promoter was found to associate with the level of adiposity at 6 and 9 years of age. Furthermore, the amount of carbohydrate in the mother diet through the pregnancy first trimester correlated with the retinoid receptor promoter methylation.
Unexpectedly, this individual epigenotype, alone, accounted for at least 25% of obesity variance in the two cohorts. This effect is surprisingly larger than the effect size of all known polymorphisms associated to obesity or T2D. If further extended and validated in well-powered studies, this information will pave the way for using epigenetic profiling at the perinatal stage to predict the onset of obesity and T2D later in life with unprecedented accuracy. More recently, independent studies have supported this conclusion as well as the technical feasibility of epigenetic profiling in predicting obesity and T2D.
Toperoff and co-workers focused their attention on a well-known risk gene for obesity and T2D termed fat mass and obesity-associated protein (FTO) . These investigators have shown that methylation of this gene represents an early marker of T2D, independent of any polymorphisms. The predictive power of these FTO epigenotypes is much larger than all FTO genetic variants so far described. Importantly, these findings were obtained using easily-accessible peripheral blood cells, which may facilitate the potential use of this information in clinical routine.
Pharmacoepigenomics and the future of T2D epigenetics
Evidence generated over the past 20 years has revealed multiple associations between specific gene polymorphisms and individual responses to most oral antidiabetic drugs . Based on this accumulated knowledge, it is anticipated that, in the not so far future, pharmacogenetic analysis will improve the management of T2D by helping the clinician in prescribing oral antidiabetic agents more effectively than it is currently possible.
It also became progressively clearer that, while genetic diversity can account for part of the heterogeneity in drug response, dose requirements and occurrance of adverse effects, the variability in response to oral antidiabetic medications will not be explained solely by investigating the genetic diversity between individual patients . Epigenomics recently achieved the potential to enhance the impact of classical pharmacogenetics on the optimization of oral antidiabetic therapy and combined profiling of genetic variability and epigenetic modifications now holds promise for personalized medicine in the field of diabetes.
Indeed, while such pharmacoepigenomic approaches have so far been exploited mainly in cancer therapy, the more recent appreciation of the significance of epigenomic modifications to T2D is expected to expand our present understanding the interindividual variability in response to oral antidiabetes agents.
The new and exciting area of epigenenetics, still largely unexplored, offers the possibility of bridging at least some of the gap between classical genetics and clinical phenotype, and offers great promise for the future.
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^ Ng SF et al. Chronic high-fat diet in fathers programs B-cell dysfunction in femaòle rat offspring. Nature 467: 963-966, 2010.
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^ Godfrey KM et al. Epigenetic gene promoter methylation at birth at birth is associated with child’s later adiposity. Diabetes 60: 1528-1534, 2011.
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