Abstract
Combinations of genetic and environmental factors contribute to the pathogenesis of type 2 diabetes (T2D); however, our knowledge of the molecular mechanisms by which these factors trigger diabetes is still limited. While genome-wide association studies have identified and characterized more than 60 genomic loci associated with T2D, recent methylome charts and reference regulatory maps obtained from tissues central to T2D can help to pinpoint the causative genetic variants. Yet, the proportion of overall trait variance explained by these genetic variants is still modest. Aging, diet, obesity, and physical inactivity represent nongenetic risk factors that may be reflected in epigenetic processes promoting T2D. Recent studies have characterized epigenetic modifications in pancreatic islets, skeletal muscle, and adipose tissue from T2D patients suggesting a central role for epigenetic mechanisms in the pathogenesis of the disease. Altered epigenetic patterns have also been found in first-degree relatives of patients with T2D and in healthy subjects born with a low birth weight suggesting that epigenetic modifications may predispose to diabetes. Lifestyle interventions including exercise and diet have also been shown to alter the epigenome in target tissues for T2D. Overall, these data propose a model where combinations of genetic, epigenetic, and nongenetic factors contribute to the risk of T2D. In this book chapter, we will explore the potential role of epigenetic mechanisms in T2D and discuss how genetics, epigenetics, and environment may interact to define the risk of developing the disease.
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References
Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12(12):1763–1768
Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7):539–553
Alibegovic AC, Hojbjerre L, Sonne MP, van Hall G, Stallknecht B, Dela F, Vaag A (2009) Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes. Diabetes 58(12):2749–2756
Alibegovic AC, Sonne MP, Hojbjerre L, Bork-Jensen J, Jacobsen S, Nilsson E, Faerch K, Hiscock N, Mortensen B, Friedrichsen M, Stallknecht B, Dela F, Vaag A (2010) Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab 299(5):E752–E763. doi:10.1152/ajpendo.00590.2009
Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the beta cell: the last ten years. Cell 148(6):1160–1171. doi:10.1016/j.cell.2012.02.010
Barres R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, Krook A, Zierath JR (2009) Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 10(3):189–198
Barres R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, Caidahl K, Krook A, O'Gorman DJ, Zierath JR (2012) Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab 15(3):405–411. doi:10.1016/j.cmet.2012.01.001
Bell CG, Finer S, Lindgren CM, Wilson GA, Rakyan VK, Teschendorff AE, Akan P, Stupka E, Down TA, Prokopenko I, Morison IM, Mill J, Pidsley R, Deloukas P, Frayling TM, Hattersley AT, McCarthy MI, Beck S, Hitman GA (2010) Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE 5(11), e14040
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23(7):781–783. doi:10.1101/gad.1787609
Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, Kellis M, Marra MA, Beaudet AL, Ecker JR, Farnham PJ, Hirst M, Lander ES, Mikkelsen TS, Thomson JA (2010) The NIH roadmap epigenomics mapping consortium. Nat Biotechnol 28(10):1045–1048. doi:10.1038/nbt1010-1045
Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, Naji A, Kaestner KH (2010) Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res 20(4):428–433
Billings LK, Florez JC (2010) The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci 1212:59–77. doi:10.1111/j.1749-6632.2010.05838.x
Bird A (2007) Perceptions of epigenetics. Nature 447(7143):396–398
Brons C, Jacobsen S, Nilsson E, Ronn T, Jensen CB, Storgaard H, Poulsen P, Groop L, Ling C, Astrup A, Vaag A (2010) Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weight-dependent manner. J Clin Endocrinol Metab 95(6):3048–3056. doi:10.1210/jc.2009-2413
Brons C, Jacobsen S, Hiscock N, White A, Nilsson E, Dunger D, Astrup A, Quistorff B, Vaag A (2012) Effects of high-fat overfeeding on mitochondrial function, glucose and fat metabolism, and adipokine levels in low-birth-weight subjects. Am J Physiol Endocrinol Metab 302(1):E43–E51. doi:10.1152/ajpendo.00095.2011
Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143(7):1084–1096. doi:10.1016/j.cell.2010.12.008
Dayeh TA, Olsson AH, Volkov P, Almgren P, Ronn T, Ling C (2013) Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. Diabetologia 56(5):1036–1046. doi:10.1007/s00125-012-2815-7
Dayeh TVP, Salö S, Hall E, Nilsson E, Olsson AH, Kirkpatrick CL, Wollheim C, Eliasson L, Rönn T, Bacos K, Ling C (2014) Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 10(3), e1004160
Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kelllis M, Kheradpour P, Lassman T, Li Q, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SC, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HS, Yip KY, Zhuang J, Bernstein BE, Green ED, Gunter C, Snyder M, Pazin MJ, Lowdon RF, Dillon LA, Adams LB, Kelly CJ, Zhang J, Wexler JR, Good PJ, Feingold EA, Crawford GE, Dekker J, Elinitski L, Farnham PJ, Giddings MC, Gingeras TR, Guigo R, Hubbard TJ, Kellis M, Kent WJ, Lieb JD, Margulies EH, Myers RM, Starnatoyannopoulos JA, Tennebaum SA, Weng Z, White KP, Wold B, Yu Y, Wrobel J, Risk BA, Gunawardena HP, Kuiper HC, Maier CW, Xie L, Chen X, Mikkelsen TS, Gillespie S, Goren A, Ram O, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Eaton ML, Dobin A, Lassmann T, Tanzer A, Lagarde J, Lin W, Xue C, Williams BA, Zaleski C, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Batut P, Bell I, Bell K, Chakrabortty S, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Li G, Luo OJ, Park E, Preall JB, Presaud K, Ribeca P, Robyr D, Ruan X, Sammeth M, Sandu KS, Schaeffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Hayashizaki Y, Reymond A, Antonarakis SE, Hannon GJ, Ruan Y, Carninci P, Sloan CA, Learned K, Malladi VS, Wong MC, Barber GP, Cline MS, Dreszer TR, Heitner SG, Karolchik D, Kirkup VM, Meyer LR, Long JC, Maddren M, Raney BJ, Grasfeder LL, Giresi PG, Battenhouse A, Sheffield NC, Showers KA, London D, Bhinge AA, Shestak C, Schaner MR, Kim SK, Zhang ZZ, Mieczkowski PA, Mieczkowska JO, Liu Z, McDaniell RM, Ni Y, Rashid NU, Kim MJ, Adar S, Zhang Z, Wang T, Winter D, Keefe D, Iyer VR, Sandhu KS, Zheng M, Wang P, Gertz J, Vielmetter J, Partridge EC, Varley KE, Gasper C, Bansal A, Pepke S, Jain P, Amrhein H, Bowling KM, Anaya M, Cross MK, Muratet MA, Newberry KM, McCue K, Nesmith AS, Fisher-Aylor KI, Pusey B, DeSalvo G, Parker SL, Balasubramanian S, Davis NS, Meadows SK, Eggleston T, Newberry JS, Levy SE, Absher DM, Wong WH, Blow MJ, Visel A, Pennachio LA, Elnitski L, Petrykowska HM, Abyzov A, Aken B, Barrell D, Barson G, Berry A, Bignell A, Boychenko V, Bussotti G, Davidson C, Despacio-Reyes G, Diekhans M, Ezkurdia I, Frankish A, Gilbert J, Gonzalez JM, Griffiths E, Harte R, Hendrix DA, Hunt T, Jungreis I, Kay M, Khurana E, Leng J, Lin MF, Loveland J, Lu Z, Manthravadi D, Mariotti M, Mudge J, Mukherjee G, Notredame C, Pei B, Rodriguez JM, Saunders G, Sboner A, Searle S, Sisu C, Snow C, Steward C, Tapanan E, Tress ML, van Baren MJ, Washieti S, Wilming L, Zadissa A, Zhengdong Z, Brent M, Haussler D, Valencia A, Raymond A, Addleman N, Alexander RP, Auerbach RK, Bettinger K, Bhardwaj N, Boyle AP, Cao AR, Cayting P, Charos A, Cheng Y, Eastman C, Euskirchen G, Fleming JD, Grubert F, Habegger L, Hariharan M, Harmanci A, Iyenger S, Jin VX, Karczewski KJ, Kasowski M, Lacroute P, Lam H, Larnarre-Vincent N, Lian J, Lindahl-Allen M, Min R, Miotto B, Monahan H, Moqtaderi Z, Mu XJ, O'Geen H, Ouyang Z, Patacsil D, Raha D, Ramirez L, Reed B, Shi M, Slifer T, Witt H, Wu L, Xu X, Yan KK, Yang X, Struhl K, Weissman SM, Tenebaum SA, Penalva LO, Karmakar S, Bhanvadia RR, Choudhury A, Domanus M, Ma L, Moran J, Victorsen A, Auer T, Centarin L, Eichenlaub M, Gruhl F, Heerman S, Hoeckendorf B, Inoue D, Kellner T, Kirchmaier S, Mueller C, Reinhardt R, Schertel L, Schneider S, Sinn R, Wittbrodt B, Wittbrodt J, Jain G, Balasundaram G, Bates DL, Byron R, Canfield TK, Diegel MJ, Dunn D, Ebersol AK, Frum T, Garg K, Gist E, Hansen RS, Boatman L, Haugen E, Humbert R, Johnson AK, Johnson EM, Kutyavin TM, Lee K, Lotakis D, Maurano MT, Neph SJ, Neri FV, Nguyen ED, Qu H, Reynolds AP, Roach V, Rynes E, Sanchez ME, Sandstrom RS, Shafer AO, Stergachis AB, Thomas S, Vernot B, Vierstra J, Vong S, Weaver MA, Yan Y, Zhang M, Akey JA, Bender M, Dorschner MO, Groudine M, MacCoss MJ, Navas P, Stamatoyannopoulos G, Stamatoyannopoulos JA, Beal K, Brazma A, Flicek P, Johnson N, Lukk M, Luscombe NM, Sobral D, Vaquerizas JM, Batzoglou S, Sidow A, Hussami N, Kyriazopoulou-Panagiotopoulou S, Libbrecht MW, Schaub MA, Miller W, Bickel PJ, Banfai B, Boley NP, Huang H, Li JJ, Noble WS, Bilmes JA, Buske OJ, Sahu AO, Kharchenko PV, Park PJ, Baker D, Taylor J, Lochovsky L (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74. doi:10.1038/nature11247
Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345(13):971–980. doi:10.1056/NEJMra002168
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102(30):10604–10609
Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, Bosco D, Berney T, Montanya E, Mohlke KL, Lieb JD, Ferrer J (2010) A map of open chromatin in human pancreatic islets. Nat Genet 42(3):255–259
Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, Beedle AS, Burdge GC, Hanson MA (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci U S A 104(31):12796–12800. doi:10.1073/pnas.0705667104
Holliday R (2006) Epigenetics: a historical overview. Epigenetics 1(2):76–80
Jacobsen SC, Brons C, Bork-Jensen J, Ribel-Madsen R, Yang B, Lara E, Hall E, Calvanese V, Nilsson E, Jorgensen SW, Mandrup S, Ling C, Fernandez AF, Fraga MF, Poulsen P, Vaag A (2012) Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men. Diabetologia. doi:10.1007/s00125-012-2717-8
Jacobsen SC, Gillberg L, Bork-Jensen J, Ribel-Madsen R, Lara E, Calvanese V, Ling C, Fernandez AF, Fraga MF, Poulsen P, Brons C, Vaag A (2014) Young men with low birthweight exhibit decreased plasticity of genome-wide muscle DNA methylation by high-fat overfeeding. Diabetologia. doi:10.1007/s00125-014-3198-8
Jimenez-Chillaron JC, Isganaitis E, Charalambous M, Gesta S, Pentinat-Pelegrin T, Faucette RR, Otis JP, Chow A, Diaz R, Ferguson-Smith A, Patti ME (2009) Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58(2):460–468. doi:10.2337/db08-0490
Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev 13(7):484–492. doi:10.1038/nrg3230
Kaati G, Bygren LO, Pembrey M, Sjostrom M (2007) Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15(7):784–790
Kameswaran V, Bramswig NC, McKenna LB, Penn M, Schug J, Hand NJ, Chen Y, Choi I, Vourekas A, Won KJ, Liu C, Vivek K, Naji A, Friedman JR, Kaestner KH (2014) Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab 19(1):135–145. doi:10.1016/j.cmet.2013.11.016
Kobberling J, Tillil H (1990) Genetic and nutritional factors in the etiology and pathogenesis of diabetes mellitus. World Rev Nutr Diet 63:102–115
Kulzer JR, Stitzel ML, Morken MA, Huyghe JR, Fuchsberger C, Kuusisto J, Laakso M, Boehnke M, Collins FS, Mohlke KL (2014) A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Am J Hum Genet 94(2):186–197. doi:10.1016/j.ajhg.2013.12.011
Li Y, He Y, Qi L, Jaddoe VW, Feskens EJ, Yang X, Ma G, Hu FB (2010) Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood. Diabetes 59(10):2400–2406. doi:10.2337/db10-0385
Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58(12):2718–2725
Ling C, Poulsen P, Simonsson S, Ronn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P, Vaag A, Groop L (2007) Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 117(11):3427–3435. doi:10.1172/JCI30938
Ling C, Del Guerra S, Lupi R, Ronn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51(4):615–622
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315–322. doi:10.1038/nature08514
Malmgren S, Spegel P, Danielsson AP, Nagorny CL, Andersson LE, Dekker Nitert M, Ridderstrale M, Mulder H, Ling C (2013) Coordinate changes in histone modifications, mRNA levels and metabolite profiles in clonal INS-1 832/13 beta-cells accompany functional adaptations to lipotoxicity. J Biol Chem. doi:10.1074/jbc.M112.422527
Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461(7265):747–753. doi:10.1038/nature08494
McCarthy M (2010) Genomics, type 2 diabetes, and obesity. N Engl J Med 363(24):2339–2350
Moran I, Akerman I, van de Bunt M, Xie R, Benazra M, Nammo T, Arnes L, Nakic N, Garcia-Hurtado J, Rodriguez-Segui S, Pasquali L, Sauty-Colace C, Beucher A, Scharfmann R, van Arensbergen J, Johnson PR, Berry A, Lee C, Harkins T, Gmyr V, Pattou F, Kerr-Conte J, Piemonti L, Berney T, Hanley N, Gloyn AL, Sussel L, Langman L, Brayman KL, Sander M, McCarthy MI, Ravassard P, Ferrer J (2012) Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab 16(4):435–448. doi:10.1016/j.cmet.2012.08.010
Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H, Mahajan A, Prokopenko I, Kang HM, Dina C, Esko T, Fraser RM, Kanoni S, Kumar A, Lagou V, Langenberg C, Luan J, Lindgren CM, Muller-Nurasyid M, Pechlivanis S, Rayner NW, Scott LJ, Wiltshire S, Yengo L, Kinnunen L, Rossin EJ, Raychaudhuri S, Johnson AD, Dimas AS, Loos RJ, Vedantam S, Chen H, Florez JC, Fox C, Liu CT, Rybin D, Couper DJ, Kao WH, Li M, Cornelis MC, Kraft P, Sun Q, van Dam RM, Stringham HM, Chines PS, Fischer K, Fontanillas P, Holmen OL, Hunt SE, Jackson AU, Kong A, Lawrence R, Meyer J, Perry JR, Platou CG, Potter S, Rehnberg E, Robertson N, Sivapalaratnam S, Stancakova A, Stirrups K, Thorleifsson G, Tikkanen E, Wood AR, Almgren P, Atalay M, Benediktsson R, Bonnycastle LL, Burtt N, Carey J, Charpentier G, Crenshaw AT, Doney AS, Dorkhan M, Edkins S, Emilsson V, Eury E, Forsen T, Gertow K, Gigante B, Grant GB, Groves CJ, Guiducci C, Herder C, Hreidarsson AB, Hui J, James A, Jonsson A, Rathmann W, Klopp N, Kravic J, Krjutskov K, Langford C, Leander K, Lindholm E, Lobbens S, Mannisto S, Mirza G, Muhleisen TW, Musk B, Parkin M, Rallidis L, Saramies J, Sennblad B, Shah S, Sigurethsson G, Silveira A, Steinbach G, Thorand B, Trakalo J, Veglia F, Wennauer R, Winckler W, Zabaneh D, Campbell H, van Duijn C, Uitterlinden AG, Hofman A, Sijbrands E, Abecasis GR, Owen KR, Zeggini E, Trip MD, Forouhi NG, Syvanen AC, Eriksson JG, Peltonen L, Nothen MM, Balkau B, Palmer CN, Lyssenko V, Tuomi T, Isomaa B, Hunter DJ, Qi L, Shuldiner AR, Roden M, Barroso I, Wilsgaard T, Beilby J, Hovingh K, Price JF, Wilson JF, Rauramaa R, Lakka TA, Lind L, Dedoussis G, Njolstad I, Pedersen NL, Khaw KT, Wareham NJ, Keinanen-Kiukaanniemi SM, Saaristo TE, Korpi-Hyovalti E, Saltevo J, Laakso M, Kuusisto J, Metspalu A, Collins FS, Mohlke KL, Bergman RN, Tuomilehto J, Boehm BO, Gieger C, Hveem K, Cauchi S, Froguel P, Baldassarre D, Tremoli E, Humphries SE, Saleheen D, Danesh J, Ingelsson E, Ripatti S, Salomaa V, Erbel R, Jockel KH, Moebus S, Peters A, Illig T, de Faire U, Hamsten A, Morris AD, Donnelly PJ, Frayling TM, Hattersley AT, Boerwinkle E, Melander O, Kathiresan S, Nilsson PM, Deloukas P, Thorsteinsdottir U, Groop LC, Stefansson K, Hu F, Pankow JS, Dupuis J, Meigs JB, Altshuler D, Boehnke M, McCarthy MI (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44(9):981–990. doi:10.1038/ng.2383
Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467(7318):963–966
Nilsson E, Jansson P, Perfilyev A, Volkov P, Pedersen M, Svensson M, Poulsen P, Ribel-Madsen R, Almgren P, Fadista J, Rönn T, Klarlund-Pedersen B, Scheele C, Vaag A, Ling C (2014) Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes 63(9):2962–2976
Nitert MD, Dayeh T, Volkov P, Elgzyri T, Hall E, Nilsson E, Yang BT, Lang S, Parikh H, Wessman Y, Weishaupt H, Attema J, Abels M, Wierup N, Almgren P, Jansson PA, Ronn T, Hansson O, Eriksson KF, Groop L, Ling C (2012) Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes 61(12):3322–3332. doi:10.2337/db11-1653
Ozanne SE, Hales CN (2002) Pre- and early postnatal nongenetic determinants of type 2 diabetes. Expert Rev Mol Med 4(24):1–14. doi:10.1017/S1462399402005240
Ozanne SE, Jensen CB, Tingey KJ, Storgaard H, Madsbad S, Vaag AA (2005) Low birthweight is associated with specific changes in muscle insulin-signalling protein expression. Diabetologia 48(3):547–552
Park JH, Stoffers DA, Nicholls RD, Simmons RA (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118(6):2316–2324
Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, van Bueren KL, Chines PS, Narisu N, Black BL, Visel A, Pennacchio LA, Collins FS (2013) Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A 110(44):17921–17926. doi:10.1073/pnas.1317023110
Pasquali L, Gaulton KJ, Rodriguez-Segui S, Mularoni L, Miguel-Escalada I, Akerman I, Tena JJ, Moran I, Gómez-Marín C, van de Bunt M, Ponsa-Cobas J, Castro N, Nammo T, Cebola I, Garcia-Hurtado J, Maestro MA, Pattou F, Piemonti L, Berney T, Gloyn AL, Ravassard P, Muller F, McCarthy MI, Ferrer J (2014) Pancreatic islet enhancer clusters enriched in type 2 diabetes risk–associated variants. Nat Genet. doi:10.1038/ng.2870
Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, Golding J (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14(2):159–166. doi:10.1038/sj.ejhg.5201538
Rakyan VK, Down TA, Balding DJ, Beck S (2011) Epigenome-wide association studies for common human diseases. Nat Rev 12(8):529–541. doi:10.1038/nrg3000
Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351(9097):173–177
Ribel-Madsen R, Fraga MF, Jacobsen S, Bork-Jensen J, Lara E, Calvanese V, Fernandez AF, Friedrichsen M, Vind BF, Hojlund K, Beck-Nielsen H, Esteller M, Vaag A, Poulsen P (2012) Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes. PLoS ONE 7(12), e51302. doi:10.1371/journal.pone.0051302
Ronn T, Poulsen P, Hansson O, Holmkvist J, Almgren P, Nilsson P, Tuomi T, Isomaa B, Groop L, Vaag A, Ling C (2008) Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia 51(7):1159–1168
Ronn T, Volkov P, Davegardh C, Dayeh T, Hall E, Olsson AH, Nilsson E, Tornberg A, Dekker Nitert M, Eriksson KF, Jones HA, Groop L, Ling C (2013) A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet 9(6), e1003572. doi:10.1371/journal.pgen.1003572
Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, O’Neill LP, Murrell A, Ling C, Constância M, Ozanne SE (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci USA 108(13):5449–5454. doi:10.1073/pnas.1019007108, Epub 2011 Mar 8
Stahl EA, Wegmann D, Trynka G, Gutierrez-Achury J, Do R, Voight BF, Kraft P, Chen R, Kallberg HJ, Kurreeman FA, Kathiresan S, Wijmenga C, Gregersen PK, Alfredsson L, Siminovitch KA, Worthington J, de Bakker PI, Raychaudhuri S, Plenge RM (2012) Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nat Genet 44(5):483–489. doi:10.1038/ng.2232
Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, Welch R, Parker SC, Boyle AP, Scott LJ, Margulies EH, Boehnke M, Furey TS, Crawford GE, Collins FS (2010) Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab 12(5):443–455
Stoffers DA, Ferrer J, Clarke WL, Habener JF (1997) Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 17(2):138–139
Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev 9(6):465–476
Toperoff G, Aran D, Kark JD, Rosenberg M, Dubnikov T, Nissan B, Wainstein J, Friedlander Y, Levy-Lahad E, Glaser B, Hellman A (2012) Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum Mol Genet 21(2):371–383. doi:10.1093/hmg/ddr472
Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segre AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Bengtsson Bostrom K, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jorgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proenca C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparso T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42(7):579–589
Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R, Calonne E, Volkmar U, Igoillo-Esteve M, Naamane N, Del Guerra S, Masini M, Bugliani M, Marchetti P, Cnop M, Eizirik DL, Fuks F (2012) DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 31(6):1405–1426. doi:10.1038/emboj.2011.503
Willems SM, Mihaescu R, Sijbrands EJ, van Duijn CM, Janssens AC (2011) A methodological perspective on genetic risk prediction studies in type 2 diabetes: recommendations for future research. Curr Diab Rep 11(6):511–518. doi:10.1007/s11892-011-0235-6
Wu H, Zhang Y (2014) Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1–2):45–68. doi:10.1016/j.cell.2013.12.019
Yang BT, Dayeh TA, Kirkpatrick CL, Taneera J, Kumar R, Groop L, Wollheim CB, Nitert MD, Ling C (2011) Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets. Diabetologia 54(2):360–367. doi:10.1007/s00125-010-1967-6
Yang BT, Dayeh TA, Volkov PA, Kirkpatrick CL, Malmgren S, Jing X, Renstrom E, Wollheim CB, Nitert MD, Ling C (2012) Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol Endocrinol 26(7):1203–1212. doi:10.1210/me.2012-1004
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Ling, C., Pasquali, L. (2016). Epigenetics in Type 2 Diabetes. In: Florez, J. (eds) The Genetics of Type 2 Diabetes and Related Traits. Springer, Cham. https://doi.org/10.1007/978-3-319-01574-3_11
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