Table of Contents Author Guidelines Submit a Manuscript
Journal of Nutrition and Metabolism
Volume 2011 (2011), Article ID 647514, 17 pages
http://dx.doi.org/10.1155/2011/647514
Review Article

T2DM: Why Epigenetics?

INSERM U986, Bicêtre Hospital, University of Paris-Sud, Le Kremlin-Bicêtre, France

Received 11 August 2011; Accepted 20 September 2011

Academic Editor: M. Pagliassotti

Copyright © 2011 Delphine Fradin and Pierre Bougnères. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Ramachandran, R. C. W. Ma, and C. Snehalatha, “Diabetes in Asia,” The Lancet, vol. 375, no. 9712, pp. 408–418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. I. Schmalhausen, Factors of Evolution, Blakiston, Philadelphia, Pa, USA, 1949.
  3. C. H. Waddington, “The epigenotype,” Endeavour, vol. 1, pp. 18–20, 1942. View at Google Scholar
  4. R. Holliday, “Epigenetics: an overview,” Developmental Genetics, vol. 15, no. 6, pp. 453–457, 1994. View at Google Scholar · View at Scopus
  5. V. E. A. Russo, Epigenetic Mechanisms of Gene Regulation, Cold Spring Harbor Laboratory Press, 1996.
  6. R. Jaenisch and A. Bird, “Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals,” Nature Genetics, vol. 33, supplement, pp. 245–254, 2003. View at Publisher · View at Google Scholar · View at Scopus
  7. E. Jablonka and M. J. Lamb, Epigenetic Inheritance and Evolution: The Lamarckian Dimension, Oxford University Press, Oxford, UK, 1995.
  8. K. G. M. M. Alberti and P. Z. Zimmet, “Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation,” Diabetic Medicine, vol. 15, no. 7, pp. 539–553, 1998. View at Publisher · View at Google Scholar · View at Scopus
  9. A. R. Folsom, M. Szklo, J. Stevens, F. Liao, R. Smith, and J. H. Eckfeldt, “A prospective study of coronary heart disease in relation to fasting insulin, glucose, and diabetes: the Atherosclerosis Risk in Communities (ARIC) Study,” Diabetes Care, vol. 20, no. 6, pp. 935–942, 1997. View at Google Scholar · View at Scopus
  10. N. Sarwar, T. Aspelund, G. Eiriksdottir et al., “Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik prospective study and systematic review,” PLoS Medicine, vol. 7, no. 5, Article ID e1000278, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. D. Vistisen, S. Colagiuri, and K. Borch-Johnsen, “Bimodal distribution of glucose is not universally useful for diagnosing diabetes,” Diabetes Care, vol. 32, no. 3, pp. 397–403, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. J. B. Meigs, D. C. Muller, D. M. Nathan, D. R. Blake, and R. Andres, “The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging,” Diabetes, vol. 52, no. 6, pp. 1475–1484, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. G. A. Nichols, T. A. Hillier, and J. B. Brown, “Normal fasting plasma glucose and risk of type 2 diabetes diagnosis,” American Journal of Medicine, vol. 121, no. 6, pp. 519–524, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. A. Tirosh, I. Shai, D. Tekes-Manova et al., “Normal fasting plasma glucose levels and type 2 diabetes in young men,” The New England Journal of Medicine, vol. 353, no. 14, pp. 1454–1462, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. A. Steinbrecher, Y. Morimoto, S. Heak et al., “The preventable proportion of type 2 diabetes by ethnicity: the multiethnic cohort,” Annals of Epidemiology, vol. 21, no. 7, pp. 526–535, 2011. View at Publisher · View at Google Scholar
  16. C. Willi, P. Bodenmann, W. A. Ghali, P. D. Faris, and J. Cornuz, “Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis,” Journal of the American Medical Association, vol. 298, no. 22, pp. 2654–2664, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. A. B. Hill, “The environment and disease: association or causation?” Proceedings of the Royal Society of Medicine, vol. 58, pp. 295–300, 1965. View at Google Scholar · View at Scopus
  18. A. J. Scheen, “Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion?” Diabetes and Metabolism, vol. 31, no. 2, pp. 5–S27, 2005. View at Google Scholar · View at Scopus
  19. E. K. Speliotes, C. J. Willer, S. I. Berndt et al., “Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index,” Nature Genetics, vol. 42, no. 11, pp. 937–948, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. I. M. Heid, A. U. Jackson, J. C. Randall et al., “Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution,” Nature Genetics, vol. 42, no. 11, pp. 949–960, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. M. I. McCarthy, “The importance of global studies of the genetics of type 2 diabetes,” Diabetes and Metabolism Journal, vol. 35, pp. 91–100, 2011. View at Google Scholar
  22. H. Furberg, Y. Kim, J. Dackor et al., “Genome-wide meta-analyses identify multiple loci associated with smoking behavior,” Nature Genetics, vol. 42, no. 5, pp. 441–447, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. S. Li, J. H. Zhao, J. Luan et al., “Genetic predisposition to obesity leads to increased risk of type 2 diabetes,” Diabetologia, vol. 54, no. 4, pp. 776–782, 2011. View at Publisher · View at Google Scholar
  24. K. Hemminki, A. Försti, and J. L. Bermejo, “The 'common disease-common variant' hypothesis and familial risks,” PLoS One, vol. 3, no. 6, Article ID e2504, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. V. Lyssenko, A. Jonsson, P. Almgren et al., “Clinical risk factors, DNA variants, and the development of type 2 diabetes,” The New England Journal of Medicine, vol. 359, no. 21, pp. 2220–2232, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. M. I. McCarthy and J. N. Hirschhorn, “Genome-wide association studies: potential next steps on a genetic journey,” Human Molecular Genetics, vol. 17, no. 2, pp. R156–R165, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. M. I. McCarthy and J. N. Hirschhorn, “Genome-wide association studies: past, present and future,” Human Molecular Genetics, vol. 17, no. 2, pp. R100–R101, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. S. L. Rutherford and S. Henikoff, “Quantitative epigenetics,” Nature Genetics, vol. 33, no. 1, pp. 6–8, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. J. A. Nettleton, N. M. McKeown, S. Kanoni et al., “Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies,” Diabetes Care, vol. 33, no. 12, pp. 2684–2691, 2010. View at Publisher · View at Google Scholar
  30. A. Barker, S. J. Sharp, N. J. Timpson et al., “Association of genetic loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children,” Diabetes, vol. 60, no. 6, pp. 1805–1812, 2011. View at Publisher · View at Google Scholar
  31. N. M. G. De Silva and T. M. Frayling, “Novel biological insights emerging from genetic studies of type 2 diabetes and related metabolic traits,” Current Opinion in Lipidology, vol. 21, no. 1, pp. 44–50, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Kelliny, U. Ekelund, L. B. Andersen et al., “Common genetic determinants of glucose homeostasis in healthy children the european youth heart study,” Diabetes, vol. 58, no. 12, pp. 2939–2945, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. I. Prokopenko, C. Langenberg, J. C. Florez et al., “Variants in MTNR1B influence fasting glucose levels,” Nature Genetics, vol. 41, no. 1, pp. 77–81, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. R. Saxena, M. F. Hivert, C. Langenberg et al., “Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge,” Nature Genetics, vol. 42, no. 2, pp. 142–148, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. R. J. Webster, N. M. Warrington, J. P. Beilby, T. M. Frayling, and L. J. Palmer, “The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI,” BMC Medical Genetics, vol. 11, no. 1, article 140, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. A. T. Kraja, D. Vaidya, J. S. Pankow et al., “A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium,” Diabetes, vol. 60, no. 4, pp. 1329–1339, 2011. View at Publisher · View at Google Scholar
  37. H. V. Lin and D. Accili, “Hormonal regulation of hepatic glucose production in health and disease,” Cell Metabolism, vol. 14, no. 1, pp. 9–19, 2011. View at Publisher · View at Google Scholar
  38. R. A. DeFronzo, R. C. Bonadonna, and E. Ferrannini, “Pathogenesis of NIDDM: a balanced overview,” Diabetes Care, vol. 15, no. 3, pp. 318–368, 1992. View at Google Scholar · View at Scopus
  39. E. Ferrannini, “Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects,” Endocrine Reviews, vol. 19, no. 4, pp. 477–490, 1998. View at Google Scholar · View at Scopus
  40. J. E. Gerich, “The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity,” Endocrine Reviews, vol. 19, no. 4, pp. 491–503, 1998. View at Google Scholar · View at Scopus
  41. S. E. Kahn, “The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes,” Diabetologia, vol. 46, no. 1, pp. 3–19, 2003. View at Google Scholar · View at Scopus
  42. M. Stumvoll, “Control of glycaemia: from molecules to men. Minkowski Lecture 2003,” Diabetologia, vol. 47, no. 5, pp. 770–781, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. R. Taylor, “Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause,” Diabetologia, vol. 51, no. 10, pp. 1781–1789, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Weyer, C. Bogardus, D. M. Mott, and R. E. Pratley, “The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus,” The Journal of Clinical Investigation, vol. 104, no. 6, pp. 787–794, 1999. View at Google Scholar · View at Scopus
  45. P. Bougnères, “Genetics of obesity and type 2 diabetes: tracking pathogenic traits during the predisease period,” Diabetes, vol. 51, no. 3, pp. S295–S303, 2002. View at Google Scholar · View at Scopus
  46. J. E. Gerich, “Contributions of insulin-resistance and insulin-secretory defects to the pathogenesis of type 2 diabetes mellitus,” Mayo Clinic Proceedings, vol. 78, no. 4, pp. 447–456, 2003. View at Google Scholar · View at Scopus
  47. A. V. Matveyenko and P. C. Butler, “Relationship between β-cell mass and diabetes onset,” Diabetes, Obesity and Metabolism, vol. 10, supplement 4, pp. 23–31, 2008. View at Publisher · View at Google Scholar
  48. N. C. Turner and J. C. Clapham, “Insulin resistance, impaired glucose tolerance and noninsulin-dependent diabetes, pathologic mechanisms and treatment: current status and therapeutic possibilities,” Progress in Drug Research, vol. 51, pp. 33–94, 1998. View at Google Scholar · View at Scopus
  49. T. W. Boesgaard, N. Grarup, T. Jørgensen, K. Borch-Johnsen, T. Hansen, and O. Pedersen, “Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people,” Diabetologia, vol. 53, no. 8, pp. 1647–1655, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. J. C. Florez, “Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes?” Diabetologia, vol. 51, no. 7, pp. 1100–1110, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. J. R. B. Perry and T. M. Frayling, “New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 11, no. 4, pp. 371–377, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. J. R. Petrie, E. R. Pearson, and C. Sutherland, “Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology,” Biochemical Pharmacology, vol. 81, pp. 471–477, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. R. M. Watanabe, “The genetics of insulin resistance: where's Waldo?” Current Diabetes Reports, vol. 10, no. 6, pp. 476–484, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. L. Groop and V. Lyssenko, “Genetic basis of β-cell dysfunction in man,” Diabetes, Obesity and Metabolism, vol. 11, supplement 4, pp. 149–158, 2009. View at Publisher · View at Google Scholar
  55. A. Doria, M. E. Patti, and C. R. Kahn, “The emerging genetic architecture of type 2 diabetes,” Cell Metabolism, vol. 8, no. 3, pp. 186–200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. S. Li, J. H. Zhao, J. Luan et al., “Physical activity attenuates the genetic predisposition to obesity in 20,000 men and women from EPIC-Norfolk prospective population study,” PLoS Medicine, vol. 7, no. 8, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. J. B. Meigs, L. A. Cupples, and P. W. F. Wilson, “Parental transmission of type 2 diabetes: the Framingham Offspring Study,” Diabetes, vol. 49, no. 12, pp. 2201–2207, 2000. View at Google Scholar · View at Scopus
  58. A. H. Barnett, C. Eff, R. D. G. Leslie, and D. A. Pyke, “Diabetes in identical twins. A study of 200 pairs,” Diabetologia, vol. 20, no. 2, pp. 87–93, 1981. View at Google Scholar · View at Scopus
  59. F. Medici, M. Hawa, A. Ianari, D. A. Pyke, and R. D. G. Leslie, “Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis,” Diabetologia, vol. 42, no. 2, pp. 146–150, 1999. View at Publisher · View at Google Scholar · View at Scopus
  60. B. Newman, J. V. Selby, M. C. King, C. Slemenda, R. Fabsitz, and G. D. Friedman, “Concordance for Type 2 (non-insulin-dependent) diabetes mellitus in male twins,” Diabetologia, vol. 30, no. 10, pp. 763–768, 1987. View at Google Scholar · View at Scopus
  61. P. Poulsen, K. Ohm Kyvik, A. Vaag, and H. Beck-Nielsen, “Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance—a population-based twin study,” Diabetologia, vol. 42, no. 2, pp. 139–145, 1999. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Vaag, J. E. Henriksen, S. Madsbad, N. Holm, and H. Beck-Nielsen, “Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus,” The Journal of Clinical Investigation, vol. 95, no. 2, pp. 690–698, 1995. View at Google Scholar · View at Scopus
  63. M. F. Fraga, E. Ballestar, M. F. Paz et al., “Epigenetic differences arise during the lifetime of monozygotic twins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 30, pp. 10604–10609, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Mill, E. Dempster, A. Caspi, B. Williams, T. Moffitt, and I. Craig, “Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene,” American Journal of Medical Genetics, Part B, vol. 141, no. 4, pp. 421–425, 2006. View at Publisher · View at Google Scholar · View at Scopus
  65. C. C. Y. Wong, A. Caspi, B. Williams et al., “A longitudinal study of epigenetic variation in twins,” Epigenetics, vol. 5, no. 6, pp. 516–526, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. E. E. Eichler, J. Flint, G. Gibson et al., “Missing heritability and strategies for finding the underlying causes of complex disease,” Nature Reviews Genetics, vol. 11, no. 6, pp. 446–450, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. B. Maher, “Personal genomes: the case of the missing heritability,” Nature, vol. 456, no. 7218, pp. 18–21, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. T. A. Manolio, F. S. Collins, N. J. Cox et al., “Finding the missing heritability of complex diseases,” Nature, vol. 461, no. 7265, pp. 747–753, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. N. J. Schork, S. S. Murray, K. A. Frazer, and E. J. Topol, “Common vs. rare allele hypotheses for complex diseases,” Current Opinion in Genetics and Development, vol. 19, no. 3, pp. 212–219, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. W. N. Frankel and N. J. Schork, “Who's afraid of epistasis?” Nature Genetics, vol. 14, no. 4, pp. 371–373, 1996. View at Google Scholar · View at Scopus
  71. J. T. Bell, N. J. Timpson, N. W. Rayner et al., “Genome-wide association scan allowing for epistasis in type 2 diabetes,” Annals of Human Genetics, vol. 75, no. 1, pp. 10–19, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. Y. S. Song, F. Wang, and M. Slatkin, “General epistatic models of the risk of complex diseases,” Genetics, vol. 186, no. 4, pp. 1467–1473, 2010. View at Publisher · View at Google Scholar
  73. C. Ober and D. Vercelli, “Gene-environment interactions in human disease: nuisance or opportunity?” Trends in Genetics, vol. 27, pp. 107–115, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. D. Thomas, “Gene-environment-wide association studies: emerging approaches,” Nature Reviews Genetics, vol. 11, no. 4, pp. 259–272, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. D. Thomas, “Methods for investigating gene-environment interactions in candidate pathway and genome-wide association studies,” Annual Review of Public Health, vol. 31, pp. 21–36, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. S. van der Sluis, M. Verhage, D. Posthuma, and C. V. Dolan, “Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies,” PLoS One, vol. 5, no. 11, Article ID e13929, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. O. Tal, E. Kisdi, and E. Jablonka, “Epigenetic contribution to covariance between relatives,” Genetics, vol. 184, no. 4, pp. 1037–1050, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. C. J. Patel, J. Bhattacharya, and A. J. Butte, “An environment-wide association study (EWAS) on type 2 diabetes mellitus,” PLoS One, vol. 5, no. 5, Article ID e10746, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. P. Alonso-Magdalena, I. Quesada, and A. Nadal, “Endocrine disruptors in the etiology of type 2 diabetes mellitus,” Nature Reviews Endocrinology, vol. 7, no. 6, pp. 346–353, 2011. View at Publisher · View at Google Scholar
  80. G. Musso, R. Gambino, and M. Cassader, “Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes,” Annual Review of Medicine, vol. 62, pp. 361–380, 2011. View at Publisher · View at Google Scholar
  81. S. H. Mehta, F. L. Brancati, S. A. Strathdee et al., “Hepatitis C virus infection and incident type 2 diabetes,” Hepatology, vol. 38, no. 1, pp. 50–56, 2003. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Diamond, “The double puzzle of diabetes,” Nature, vol. 423, no. 6940, pp. 599–602, 2003. View at Publisher · View at Google Scholar · View at Scopus
  83. N. A. Christakis and J. H. Fowler, “The spread of obesity in a large social network over 32 years,” The New England Journal of Medicine, vol. 357, no. 4, pp. 370–379, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. J. Liu, M. Morgan, K. Hutchison, and V. D. Calhoun, “A study of the influence of sex on genome wide methylation,” PLoS One, vol. 5, no. 4, Article ID e10028, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Zhang, L. Cheng, J. A. Badner et al., “Genetic control of individual differences in gene-specific methylation in human brain,” American Journal of Human Genetics, vol. 86, no. 3, pp. 411–419, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. A. M. Casto and M. W. Feldman, “Genome-wide association study SNPS in the human genome diversity project populations: does selection affect unlinked SNPS with shared trait associations?” PLoS Genetics, vol. 7, no. 1, Article ID e1001266, 2011. View at Publisher · View at Google Scholar
  87. G. Coop, J. K. Pickrell, J. Novembre et al., “The role of geography in human adaptation,” PLoS Genetics, vol. 5, no. 6, Article ID e1000500, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. M. Stoneking and F. Delfin, “The human genetic history of East Asia: weaving a complex tapestry,” Current Biology, vol. 20, no. 4, pp. R188–R193, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. A. M. Hancock, D. B. Witonsky, G. Alkorta-Aranburu et al., “Adaptations to climate-mediated selective pressures in humans,” PLoS Genetics, vol. 7, no. 4, Article ID e1001375, 2011. View at Publisher · View at Google Scholar
  90. A. M. Hancock, D. B. Witonsky, A. S. Gordon et al., “Adaptations to climate in candidate genes for common metabolic disorders,” PLoS Genetics, vol. 4, no. 2, p. e32, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. Y. C. Klimentidis, M. Abrams, J. Wang, J. R. Fernandez, and D. B. Allison, “Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions,” Human Genetics, vol. 129, pp. 407–418, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. A. P. Feinberg and R. A. Irizarry, “Evolution in health and medicine Sackler colloquium: stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, supplement 1, pp. 1757–1764, 2010. View at Publisher · View at Google Scholar
  93. E. Jablonka and M. J. Lamb, Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life, MIT Press, Cambridge, Mass, USA, 2005.
  94. T. Kouzarides, “Chromatin modifications and their function,” Cell, vol. 128, no. 4, pp. 693–705, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. N. Avvakumov and J. Côté, “The MYST family of histone acetyltransferases and their intimate links to cancer,” Oncogene, vol. 26, no. 37, pp. 5395–5407, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. M. Haberland, R. L. Montgomery, and E. N. Olson, “The many roles of histone deacetylases in development and physiology: implications for disease and therapy,” Nature Reviews Genetics, vol. 10, no. 1, pp. 32–42, 2009. View at Publisher · View at Google Scholar · View at Scopus
  97. M. D. Shahbazian and M. Grunstein, “Functions of Site-Specific histone acetylation and deacetylation,” Annual Review of Biochemistry, vol. 76, pp. 75–100, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. Z. Wang, C. Zang, J. A. Rosenfeld et al., “Combinatorial patterns of histone acetylations and methylations in the human genome,” Nature Genetics, vol. 40, no. 7, pp. 897–903, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. E. Bártová, J. Krejci, A. Harničarová, G. Galiová, and S. Kozubek, “Histone modifications and nuclear architecture: a review,” Journal of Histochemistry and Cytochemistry, vol. 56, no. 8, pp. 711–721, 2008. View at Publisher · View at Google Scholar
  100. R. Marmorstein and R. C. Trievel, “Histone modifying enzymes: structures, mechanisms, and specificities,” Biochimica et Biophysica Acta, vol. 1789, no. 1, pp. 58–68, 2009. View at Publisher · View at Google Scholar
  101. S. D. Fouse, R. P. Nagarajan, and J. F. Costello, “Genome-scale DNA methylation analysis,” Epigenomics, vol. 2, no. 1, pp. 105–117, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. A. P. Bird, “CpG-rich islands and the function of DNA methylation,” Nature, vol. 321, no. 6067, pp. 209–213, 1986. View at Google Scholar · View at Scopus
  103. A. Bird, M. Taggart, and M. Frommer, “A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA,” Cell, vol. 40, no. 1, pp. 91–99, 1985. View at Google Scholar
  104. E. S. Lander, L. M. Linton, B. Birren et al., “Initial sequencing and analysis of the human genome,” Nature, vol. 409, no. 6822, pp. 860–921, 2001. View at Publisher · View at Google Scholar · View at Scopus
  105. F. Larsen, G. Gundersen, R. Lopez, and H. Prydz, “CpG islands as gene markers in the human genome,” Genomics, vol. 13, no. 4, pp. 1095–1107, 1992. View at Publisher · View at Google Scholar · View at Scopus
  106. S. Saxonov, P. Berg, and D. L. Brutlag, “A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 5, pp. 1412–1417, 2006. View at Publisher · View at Google Scholar · View at Scopus
  107. M. Weber, I. Hellmann, M. B. Stadler et al., “Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome,” Nature Genetics, vol. 39, no. 4, pp. 457–466, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Doi, I. H. Park, B. Wen et al., “Differential methylation of tissue-and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts,” Nature Genetics, vol. 41, no. 12, pp. 1350–1353, 2009. View at Publisher · View at Google Scholar · View at Scopus
  109. R. A. Irizarry, C. Ladd-Acosta, B. Wen et al., “The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores,” Nature Genetics, vol. 41, no. 2, pp. 178–186, 2009. View at Publisher · View at Google Scholar · View at Scopus
  110. R. R. Meehan, J. D. Lewis, S. McKay, E. L. Kleiner, and A. P. Bird, “Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs,” Cell, vol. 58, no. 3, pp. 499–507, 1989. View at Google Scholar · View at Scopus
  111. R. Meehan, J. Lewis, S. Cross, X. Nan, P. Jeppesen, and A. Bird, “Transcriptional repression by methylation of CpG,” Journal of Cell Science, vol. 103, no. 16, pp. 9–14, 1992. View at Google Scholar · View at Scopus
  112. K. V. Morris, “Non-coding RNAs, epigenetic memory, and the passage of information to progeny,” RNA Biology, vol. 6, no. 3, pp. 34–39, 2009. View at Google Scholar · View at Scopus
  113. M. Rassoulzadegan, V. Grandjean, P. Gounon, S. Vincent, I. Gillot, and F. Cuzin, “RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse,” Nature, vol. 441, no. 7092, pp. 469–474, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. S. K. Zaidi, D. W. Young, M. Montecino et al., “Bookmarking the genome: maintenance of epigenetic information,” The Journal of Biological Chemistry, vol. 286, no. 21, pp. 18355–18361, 2011. View at Publisher · View at Google Scholar
  115. A. Aravin, D. Gaidatzis, S. Pfeffer et al., “A novel class of small RNAs bind to MILI protein in mouse testes,” Nature, vol. 442, no. 7099, pp. 203–207, 2006. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Brennecke, C. D. Malone, A. A. Aravin, R. Sachidanandam, A. Stark, and G. J. Hannon, “An epigenetic role for maternally inherited piRNAs in transposon silencing,” Science, vol. 322, no. 5906, pp. 1387–1392, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. K. Okamura, W. J. Chung, J. G. Ruby, H. Guo, D. P. Bartel, and E. C. Lai, “The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs,” Nature, vol. 453, no. 7196, pp. 803–806, 2008. View at Publisher · View at Google Scholar · View at Scopus
  118. M. S. Klenov, S. A. Lavrov, A. D. Stolyarenko et al., “Repeat-associated siRNAs cause chromatin silencing of retrotransposons in the Drosophila melanogaster germline,” Nucleic Acids Research, vol. 35, no. 16, pp. 5430–5438, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. J. L.S. Esguerra, C. Bolmeson, C. M. Cilio, and L. Eliasson, “Differential glucose-regulation of microRNAs in pancreatic islets of non-obese type 2 diabetes model Goto-Kakizaki rat,” PLoS One, vol. 6, no. 4, Article ID e18613, 2011. View at Publisher · View at Google Scholar
  120. S. L. Fernandez-Valverde, R. J. Taft, and J. S. Mattick, “MicroRNAs in β-cell biology, insulin resistance, diabetes and its complications,” Diabetes, vol. 60, no. 7, pp. 1825–1831, 2011. View at Publisher · View at Google Scholar
  121. C. Guay, E. Roggli, V. Nesca, C. Jacovetti, and R. Regazzi, “Diabetes mellitus, a microRNA-related disease?” Translational Research, vol. 157, no. 4, pp. 253–264, 2011. View at Publisher · View at Google Scholar
  122. E. Pasmant, A. Sabbagh, M. Vidaud, and I. Bièche, “ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS,” The FASEB Journal, vol. 25, no. 2, pp. 444–448, 2011. View at Publisher · View at Google Scholar
  123. L. S. Wilkinson, W. Davies, and A. R. Isles, “Genomic imprinting effects on brain development and function,” Nature Reviews Neuroscience, vol. 8, no. 11, pp. 832–843, 2007. View at Publisher · View at Google Scholar · View at Scopus
  124. I. K. Temple and J. P.H. Shield, “6q24 transient neonatal diabetes,” Reviews in Endocrine and Metabolic Disorders, vol. 11, no. 3, pp. 199–204, 2010. View at Publisher · View at Google Scholar
  125. J. T. Bell and T. D. Spector, “A twin approach to unraveling epigenetics,” Trends in Genetics, vol. 27, no. 3, pp. 116–125, 2011. View at Publisher · View at Google Scholar
  126. B. T. Heijmans, D. Kremer, E. W. Tobi, D. I. Boomsma, and P. E. Slagboom, “Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus,” Human Molecular Genetics, vol. 16, no. 5, pp. 547–554, 2007. View at Publisher · View at Google Scholar · View at Scopus
  127. Z. A. Kaminsky, T. Tang, S. C. Wang et al., “DNA methylation profiles in monozygotic and dizygotic twins,” Nature Genetics, vol. 41, no. 2, pp. 240–245, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. M. Ollikainen, K. R. Smith, E. J. H. Joo et al., “DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome,” Human Molecular Genetics, vol. 19, no. 21, Article ID ddq336, pp. 4176–4188, 2010. View at Publisher · View at Google Scholar · View at Scopus
  129. M. P. Boks, E. M. Derks, D. J. Weisenberger et al., “The relationship of DNA methylation with age, gender and genotype in twins and healthy controls,” PLoS One, vol. 4, no. 8, Article ID e6767, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. J. R. Gibbs, M. P. van der Brug, D. G. Hernandez et al., “Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain,” PLoS Genetics, vol. 6, no. 5, Article ID e1000952, 2010. View at Publisher · View at Google Scholar · View at Scopus
  131. H. T. Bjornsson, M. I. Sigurdsson, M. D. Fallin et al., “Intra-individual change over time in DNA methylation with familial clustering,” Journal of the American Medical Association, vol. 299, no. 24, pp. 2877–2883, 2008. View at Publisher · View at Google Scholar · View at Scopus
  132. F. Johannes, E. Porcher, F. K. Teixeira et al., “Assessing the impact of transgenerational epigenetic variation on complex traits,” PLoS Genetics, vol. 5, no. 6, Article ID e1000530, 2009. View at Publisher · View at Google Scholar · View at Scopus
  133. M. Kasowski, F. Grubert, C. Heffelfinger et al., “Variation in transcription factor binding among humans,” Science, vol. 328, no. 5975, pp. 232–235, 2010. View at Publisher · View at Google Scholar · View at Scopus
  134. R. McDaniell, B. K. Lee, L. Song et al., “Heritable individual-specific and allele-specific chromatin signatures in humans,” Science, vol. 328, no. 5975, pp. 235–239, 2010. View at Publisher · View at Google Scholar · View at Scopus
  135. E. L. Meaburn, L. C. Schalkwyk, and J. Mill, “Allele-specific methylation in the human genome: implications for genetic studies of complex disease,” Epigenetics, vol. 5, no. 7, pp. 578–582, 2010. View at Publisher · View at Google Scholar · View at Scopus
  136. C. G. Bell, S. Finer, C. M. Lindgren et al., “Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus,” PLoS One, vol. 5, no. 11, Article ID e14040, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. M. D. Anway, A. S. Cupp, N. Uzumcu, and M. K. Skinner, “Toxicology: epigenetic transgenerational actions of endocrine disruptors and male fertility,” Science, vol. 308, no. 5727, pp. 1466–1469, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. L. Shi, S. Ko, S. Kim et al., “Loss of androgen receptor in aging and oxidative stress through Myb protooncoprotein-regulated reciprocal chromatin dynamics of p53 and poly(ADP-ribose) polymerase PARP-1,” The Journal of Biological Chemistry, vol. 283, no. 52, pp. 36474–36485, 2008. View at Publisher · View at Google Scholar · View at Scopus
  139. M. E. Pembrey, L. O. Bygren, G. Kaati et al., “Sex-specific, male-line transgenerational responses in humans,” European Journal of Human Genetics, vol. 14, no. 2, pp. 159–166, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. S. F. Ng, R. C. Y. Lin, D. R. Laybutt, R. Barres, J. A. Owens, and M. J. Morris, “Chronic high-fat diet in fathers programs β 2-cell dysfunction in female rat offspring,” Nature, vol. 467, no. 7318, pp. 963–966, 2010. View at Publisher · View at Google Scholar · View at Scopus
  141. F. A. Champagne, “Epigenetic mechanisms and the transgenerational effects of maternal care,” Frontiers in Neuroendocrinology, vol. 29, no. 3, pp. 386–397, 2008. View at Publisher · View at Google Scholar
  142. P. O. McGowan and M. Szyf, “Environmental epigenomics: understanding the effects of parental care on the epigenome,” Essays in Biochemistry, vol. 48, no. 1, pp. 275–287, 2010. View at Google Scholar
  143. E. Whitelaw and D. I. K. Martin, “Retrotransposons as epigenetic mediators of phenotypic variation in mammals,” Nature Genetics, vol. 27, no. 4, pp. 361–365, 2001. View at Publisher · View at Google Scholar · View at Scopus
  144. V. K. Rakyan and S. Beck, “Epigenetic variation and inheritance in mammals,” Current Opinion in Genetics and Development, vol. 16, no. 6, pp. 573–577, 2006. View at Publisher · View at Google Scholar · View at Scopus
  145. R. A. Waterland, R. Kellermayer, E. Laritsky et al., “Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles,” PLoS Genetics, vol. 6, no. 12, Article ID e1001252, 10 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  146. P. D. Gluckman, M. A. Hanson, H. G. Spencer, and P. Bateson, “Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies,” Proceedings of the Royal Society B, vol. 272, no. 1564, pp. 671–677, 2005. View at Publisher · View at Google Scholar · View at Scopus
  147. M. J. West-Eberhart, Developmental Plasticity and Evolution, Oxford University Press, New York, NY, USA, 2003.
  148. K. Godfrey, Developmental Origins of Health and Disease, Cambridge University Press, Cambridge, UK, 2006.
  149. D. J. P. Barker, “Deprivation in infancy and risk of ischaemic heart disease,” The Lancet, vol. 337, no. 8747, p. 981, 1991. View at Google Scholar · View at Scopus
  150. D. J. P. Barker and C. Osmond, “Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales,” The Lancet, vol. 1, no. 8489, pp. 1077–1081, 1986. View at Google Scholar · View at Scopus
  151. D. J. P. Barker, P. D. Winter, C. Osmond, B. Margetts, and S. J. Simmonds, “Weight in infancy and death from ischaemic heart disease,” The Lancet, vol. 2, no. 8663, pp. 577–580, 1989. View at Google Scholar · View at Scopus
  152. C. E. Stein, C. H. D. Fall, K. Kumaran, C. Osmond, V. Cox, and D. J. P. Barker, “Fetal growth and coronary heart disease in South India,” The Lancet, vol. 348, no. 9037, pp. 1269–1273, 1996. View at Publisher · View at Google Scholar · View at Scopus
  153. S. R. de Rooij, R. C. Painter, D. I. W. Phillips et al., “Impaired insulin secretion after prenatal exposure to the Dutch famine,” Diabetes Care, vol. 29, no. 8, pp. 1897–1901, 2006. View at Publisher · View at Google Scholar · View at Scopus
  154. R. C. Painter, T. J. Roseboom, and O. P. Bleker, “Prenatal exposure to the Dutch famine and disease in later life: an overview,” Reproductive Toxicology, vol. 20, no. 3, pp. 345–352, 2005. View at Publisher · View at Google Scholar
  155. Y. Li, Y. He, L. Qi et al., “Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood,” Diabetes, vol. 59, no. 10, pp. 2400–2406, 2010. View at Publisher · View at Google Scholar · View at Scopus
  156. B. Mazumder, D. Almond, K. Park, E. M. Crimmins, and C. E. Finch, “Lingering prenatal effects of the 1918 influenza pandemic on cardiovascular disease,” Journal of Developmental Origins of Health and Disease, vol. 1, pp. 26–34, 2010. View at Google Scholar
  157. P. D. Gluckman and M. A. Hanson, “Living with the past: evolution, development, and patterns of disease,” Science, vol. 305, no. 5691, pp. 1733–1736, 2004. View at Publisher · View at Google Scholar · View at Scopus
  158. E. W. Tobi, L. H. Lumey, R. P. Talens et al., “DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific,” Human Molecular Genetics, vol. 18, no. 21, pp. 4046–4053, 2009. View at Publisher · View at Google Scholar · View at Scopus
  159. B. T. Heijmans, E. W. Tobi, A. D. Stein et al., “Persistent epigenetic differences associated with prenatal exposure to famine in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 44, pp. 17046–17049, 2008. View at Publisher · View at Google Scholar · View at Scopus
  160. E. W. Tobi, B. T. Heijmans, D. Kremer et al., “DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age,” Epigenetics, vol. 6, no. 2, pp. 171–176, 2011. View at Publisher · View at Google Scholar
  161. I. C. McMillen and J. S. Robinson, “Developmental origins of the metabolic syndrome: prediction, plasticity, and programming,” Physiological Reviews, vol. 85, no. 2, pp. 571–633, 2005. View at Publisher · View at Google Scholar · View at Scopus
  162. K. A. Lillycrop, E. S. Phillips, A. A. Jackson, M. A. Hanson, and G. C. Burdge, “Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring,” Journal of Nutrition, vol. 135, no. 6, pp. 1382–1386, 2005. View at Google Scholar · View at Scopus
  163. K. A. Lillycrop, J. L. Slater-Jefferies, M. A. Hanson, K. M. Godfrey, A. A. Jackson, and G. C. Burdge, “Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications,” British Journal of Nutrition, vol. 97, no. 6, pp. 1064–1073, 2007. View at Publisher · View at Google Scholar · View at Scopus
  164. P. D. Gluckman, K. A. Lillycrop, M. H. Vickers et al., “Metabolic plasticity during mammalian development is directionally dependent on early nutritional status,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 31, pp. 12796–12800, 2007. View at Publisher · View at Google Scholar · View at Scopus
  165. M. H. Vickers, P. D. Gluckman, A. H. Coveny et al., “Neonatal leptin treatment reverses developmental programming,” Endocrinology, vol. 146, no. 10, pp. 4211–4216, 2005. View at Publisher · View at Google Scholar · View at Scopus
  166. Q. Fu, X. Yu, C. W. Callaway, R. H. Lane, and R. A. McKnight, “Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene,” The FASEB Journal, vol. 23, no. 8, pp. 2438–2449, 2009. View at Publisher · View at Google Scholar · View at Scopus
  167. B. E. Levin, “Epigenetic influences on food intake and physical activity level: review of animal studies,” Obesity, vol. 16, supplement 3, pp. S51–S54, 2008. View at Publisher · View at Google Scholar
  168. X. Ke, M. E. Schober, R. A. McKnight et al., “Intrauterine growth retardation affects expression and epigenetic characteristics of the rat hippocampal glucocorticoid receptor gene,” Physiological Genomics, vol. 42, no. 2, pp. 177–189, 2010. View at Publisher · View at Google Scholar · View at Scopus
  169. K. M. Aagaard-Tillery, K. Grove, J. Bishop et al., “Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome,” Journal of Molecular Endocrinology, vol. 41, no. 1-2, pp. 91–102, 2008. View at Publisher · View at Google Scholar · View at Scopus
  170. M. N. Edelmann and A. P. Auger, “Epigenetic impact of simulated maternal grooming on estrogen receptor alpha within the developing amygdala,” Brain, Behavior, and Immunity, vol. 25, no. 7, pp. 1299–1304, 2011. View at Publisher · View at Google Scholar
  171. I. C. G. Weaver, M. J. Meaney, and M. Szyf, “Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 9, pp. 3480–3485, 2006. View at Publisher · View at Google Scholar · View at Scopus
  172. P. M. Plotsky, K. V. Thrivikraman, C. B. Nemeroff, C. Caldji, S. Sharma, and M. J. Meaney, “Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring,” Neuropsychopharmacology, vol. 30, no. 12, pp. 2192–2204, 2005. View at Publisher · View at Google Scholar · View at Scopus
  173. C. Thomas, E. Hyppönen, and C. Power, “Obesity and type 2 diabetes risk in midadult life: the role of childhood adversity,” Pediatrics, vol. 121, no. 5, pp. e1240–e1249, 2008. View at Publisher · View at Google Scholar · View at Scopus
  174. T. Tamayo, H. Christian, and W. Rathmann, “Impact of early psychosocial factors (childhood socioeconomic factors and adversities) on future risk of type 2 diabetes, metabolic disturbances and obesity: a systematic review,” BMC Public Health, vol. 10, article 525, 2010. View at Publisher · View at Google Scholar · View at Scopus
  175. M. Jiang, Y. Zhang, M. Liu et al., “Hypermethylation of hepatic glucokinase and L-type pyruvate kinase promoters in high-fat diet-induced obese rats,” Endocrinology, vol. 152, no. 4, pp. 1284–1289, 2011. View at Publisher · View at Google Scholar
  176. A. Lomba, J. A. Martínez, D. F. García-Díaz et al., “Weight gain induced by an isocaloric pair-fed high fat diet: a nutriepigenetic study on FASN and NDUFB6 gene promoters,” Molecular Genetics and Metabolism, vol. 101, no. 2-3, pp. 273–278, 2010. View at Publisher · View at Google Scholar
  177. S. Ehrlich, D. Weiss, R. Burghardt et al., “Promoter specific DNA methylation and gene expression of POMC in acutely underweight and recovered patients with anorexia nervosa,” Journal of Psychiatric Research, vol. 44, no. 13, pp. 827–833, 2010. View at Publisher · View at Google Scholar · View at Scopus
  178. V. Fonseca, A. Dicker-Brown, S. Ranganathan et al., “Effects of a high-fat-sucrose diet on enzymes in homocysteine metabolism in the rat,” Metabolism, vol. 49, no. 6, pp. 736–741, 2000. View at Google Scholar · View at Scopus
  179. P. Tessari, E. Kiwanuka, A. Coracina et al., “Insulin in methionine and homocysteine kinetics in healthy humans: plasma vs. intracellular models,” American Journal of Physiology, vol. 288, no. 6, pp. E1270–E1276, 2005. View at Publisher · View at Google Scholar
  180. A. Dicker-Brown, V. A. Fonseca, L. M. Fink, and P. A. Kern, “The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-β-synthase: studies in hepatocytes,” Atherosclerosis, vol. 158, no. 2, pp. 297–301, 2001. View at Publisher · View at Google Scholar · View at Scopus
  181. S. Ratnam, K. N. Maclean, R. L. Jacobs, M. E. Brosnan, J. P. Kraus, and J. T. Brosnan, “Hormonal regulation of cystathionine β-synthase expression in liver,” The Journal of Biological Chemistry, vol. 277, no. 45, pp. 42912–42918, 2002. View at Publisher · View at Google Scholar · View at Scopus
  182. E.-P. I. Chiang, Y.-C. Wang, W.-W. Chen, and F.-Y. Tang, “Effects of insulin and glucose on cellular metabolic fluxes in homocysteine transsulfuration, remethylation, sdenosylmethionine synthesis, and global deoxyribonucleic acid methylation,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 3, pp. 1017–1025, 2009. View at Publisher · View at Google Scholar
  183. E. P. Wijekoon, B. Hall, S. Ratnam, M. E. Brosnan, S. H. Zeisel, and J. T. Brosnan, “Homocysteine metabolism in ZDF (type 2) diabetic rats,” Diabetes, vol. 54, no. 11, pp. 3245–3251, 2005. View at Publisher · View at Google Scholar · View at Scopus
  184. S. P. Liu, Y. S. Li, Y. J. Chen et al., “Glycine N-methyltransferase-/- mice develop chronic hepatitis and glycogen storage disease in the liver,” Hepatology, vol. 46, no. 5, pp. 1413–1425, 2007. View at Publisher · View at Google Scholar · View at Scopus
  185. P. Tessari, A. Coracina, E. Kiwanuka et al., “Effects of insulin on methionine and homocysteine kinetics in type 2 diabetes with nephropathy,” Diabetes, vol. 54, no. 10, pp. 2968–2976, 2005. View at Publisher · View at Google Scholar · View at Scopus
  186. V. K. Rakyan, T. A. Down, S. Maslau et al., “Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains,” Genome Research, vol. 20, no. 4, pp. 434–439, 2010. View at Publisher · View at Google Scholar · View at Scopus
  187. S. Shen, J. Sandoval, V. A. Swiss et al., “Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency,” Nature Neuroscience, vol. 11, no. 9, pp. 1024–1034, 2008. View at Publisher · View at Google Scholar · View at Scopus
  188. A. E. Teschendorff, U. Menon, A. Gentry-Maharaj et al., “Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer,” Genome Research, vol. 20, no. 4, pp. 440–446, 2010. View at Publisher · View at Google Scholar · View at Scopus
  189. B. C. Christensen, E. A. Houseman, C. J. Marsit et al., “Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CPG island context,” PLoS Genetics, vol. 5, no. 8, Article ID e1000602, 2009. View at Publisher · View at Google Scholar · View at Scopus
  190. F. Z. Marques, M. A. Markus, and B. J. Morris, “The molecular basis of longevity, and clinical implications,” Maturitas, vol. 65, no. 2, pp. 87–91, 2010. View at Publisher · View at Google Scholar · View at Scopus
  191. A. P. Feinberg, R. A. Irizarry, D. Fradin et al., “Personalized epigenomic signatures that are stable over time and covary with body mass index,” Science Translational Medicine, vol. 2, no. 49, article 49ra67, 2010. View at Publisher · View at Google Scholar
  192. M. H. Jiang, J. Fei, M. S. Lan et al., “Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential,” Diabetologia, vol. 51, no. 8, pp. 1525–1533, 2008. View at Publisher · View at Google Scholar · View at Scopus
  193. V. K. Mootha, C. M. Lindgren, K. F. Eriksson et al., “PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes,” Nature Genetics, vol. 34, no. 3, pp. 267–273, 2003. View at Publisher · View at Google Scholar · View at Scopus
  194. T. Rönn, P. Poulsen, O. Hansson et al., “Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle,” Diabetologia, vol. 51, no. 7, pp. 1159–1168, 2008. View at Publisher · View at Google Scholar · View at Scopus
  195. C. Ling, P. Poulsen, S. Simonsson et al., “Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle,” The Journal of Clinical Investigation, vol. 117, no. 11, pp. 3427–3435, 2007. View at Publisher · View at Google Scholar · View at Scopus
  196. D. L. Foley, J. M. Craig, R. Morley et al., “Prospects for epigenetic epidemiology,” American Journal of Epidemiology, vol. 169, no. 4, pp. 389–400, 2009. View at Publisher · View at Google Scholar · View at Scopus
  197. E. Jablonka, “Epigenetic epidemiology,” International Journal of Epidemiology, vol. 33, no. 5, pp. 929–935, 2004. View at Publisher · View at Google Scholar · View at Scopus
  198. C. L. Relton and G. D. Smith, “Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment,” PLoS Medicine, vol. 7, no. 10, Article ID e1000356, 2010. View at Publisher · View at Google Scholar · View at Scopus
  199. H. T. Bjornsson, M. Daniele Fallin, and A. P. Feinberg, “An integrated epigenetic and genetic approach to common human disease,” Trends in Genetics, vol. 20, no. 8, pp. 350–358, 2004. View at Publisher · View at Google Scholar · View at Scopus
  200. F. Eckhardt, J. Lewin, R. Cortese et al., “DNA methylation profiling of human chromosomes 6, 20 and 22,” Nature Genetics, vol. 38, no. 12, pp. 1378–1385, 2006. View at Publisher · View at Google Scholar · View at Scopus
  201. F. Song, S. Mahmood, S. Ghosh et al., “Tissue specific differentially methylated regions (TDMR): changes in DNA methylation during development,” Genomics, vol. 93, no. 2, pp. 130–139, 2009. View at Publisher · View at Google Scholar · View at Scopus
  202. H. Ji, L. I. R. Ehrlich, J. Seita et al., “Comprehensive methylome map of lineage commitment from haematopoietic progenitors,” Nature, vol. 467, no. 7313, pp. 338–342, 2010. View at Publisher · View at Google Scholar · View at Scopus
  203. H. Cui, M. Cruz-Correa, F. M. Giardiello et al., “Loss of IGF2 imprinting: a potential marker of colorectal cancer risk,” Science, vol. 299, no. 5613, pp. 1753–1755, 2003. View at Publisher · View at Google Scholar · View at Scopus
  204. R. P. Talens, D. I. Boomsma, E. W. Tobi et al., “Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology,” The FASEB Journal, vol. 24, no. 9, pp. 3135–3144, 2010. View at Publisher · View at Google Scholar · View at Scopus
  205. V. K. Rakyan, T. A. Down, N. P. Thorne et al., “An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs),” Genome Research, vol. 18, no. 9, pp. 1518–1529, 2008. View at Publisher · View at Google Scholar · View at Scopus
  206. S. L. Berger, T. Kouzarides, R. Shiekhattar, and A. Shilatifard, “An operational definition of epigenetics,” Genes and Development, vol. 23, no. 7, pp. 781–783, 2009. View at Publisher · View at Google Scholar · View at Scopus
  207. E. H. Simpson, “The interpretation of interaction in contingency tables,” Journal of the Royal Statistical Society, vol. 13, pp. 238–241, 1903. View at Google Scholar
  208. H. A. Lawson, A. Lee, G. L. Fawcett et al., “The importance of context to the genetic architecture of diabetes-related traits is revealed in a genome-wide scan of a LG/J × SM/J murine model,” Mammalian Genome, vol. 22, pp. 197–208, 2011. View at Publisher · View at Google Scholar · View at Scopus