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Epigenetics of Diabetic Nephropathy

  • Harvest F. Gu
Reference work entry

Abstract

Diabetes has become epidemic worldwide, and the patients with diabetes often develop diabetic nephropathy (DN). This complication is the most common cause of end-stage renal disease, which requires treatment with dialysis or kidney transplantation. The treatment costs of DN in patients are increasing and impose a substantial burden on the healthcare system. DN is a complex disease reflecting the interplay between genetic, nongenetic, and epigenetic factors. Emerging evidence has demonstrated that genomic DNA methylation changes, chromatin histone modifications, and noncoding RNA dysregulation are involved in the pathogenesis of DN. Furthermore, the reversibility of these epigenetic effects in DN is the prerequisite for interactions with the environment. Therefore, researchers have put their efforts to identify the inherited and modifiable epigenetic features associated with DN in order to improve understanding of the pathogenesis of DN and to discover new targets that may act as biomarkers for the prediction of DN. In this chapter, the current design, approach, and biological material used in epigenetic study of DN are reviewed. Recent studies of epigenetic effects in DN are summarized, and further investigation of epigenetic mechanisms in DN is discussed.

Keywords

Albuminuria Diabetic nephropathy DNA methylation Epigenetics End-stage renal disease Genetic polymorphism Histone modification MicroRNA dysregulation Type 1 diabetes Type 2 diabetes 

List of Abbreviations

ADA

American Diabetes Association

BMI

Body mass index

DN

Diabetic nephropathy

ESRD

End-stage renal disease

GDM

Gestational diabetes mellitus

IDF

International Diabetes Federation

IGFBP-1

Insulin-like growth factor-binding protein-1

LCL

Lymphoblastoid cell lines

NGT

Normal glucose tolerance

PBL

Peripheral blood leukocytes

SLC30A8

Solute carrier family 30 members 8

T1D

Type 1 diabetes

T2D

Type 2 diabetes

UAE

Urinary albumin excretion

UTR

Untranslated regions

References

  1. Al-Rubeaan K, Al-Manaa HA, Khoja TA, Ahmad NA, Al-Sharqawi AH, Siddiqui K, Alnaqeb D, Aburisheh KH, Youssef AM, Al-Batel A, Alotaibi MS, Al-Gamdi AA (2015) Epidemiology of abnormal glucose metabolism in a country facing its epidemic: SAUDI-DM study. J Diabetes 7(5):622–632CrossRefGoogle Scholar
  2. Alvarez ML, Khosroheidari M, Eddy E, Kiefer J (2013) Role of microRNA 1207-5P and its host gene, the long non-coding RNA Pvt1, as mediators of extracellular matrix accumulation in the kidney: implications for diabetic nephropathy. PLoS One 8(10):e77468CrossRefGoogle Scholar
  3. American Diabetes Association (2009) Nephropathy in diabetes (position statement). Diabetes Care 32(Suppl 1):S13–S61CrossRefGoogle Scholar
  4. Barkai L, Tombacz A (2001) Alterations in insulin-like growth factor binding protein-1 and sex hormone binding globulin levels in type 1 diabetic adolescents with microalbuminuria. Diabetes Care 24(3):605–606CrossRefGoogle Scholar
  5. Bell CG, Teschendorff AE, Rakyan VK, Maxwell AP, Beck S, Savage DA (2010) Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genet 3:33.  https://doi.org/10.1186/1755-8794-3-33CrossRefGoogle Scholar
  6. Bock F, Shahzad K, Wang H, Stoyanov S, Wolter J, Dong W, Pelicci PG, Kashif M, Ranjan S, Schmidt S, Ritzel R, Schwenger V, Reymann KG, Esmon CT, Madhusudhan T, Nawroth PP, Isermann B (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci USA 110(2):648–653CrossRefGoogle Scholar
  7. Brennan EP, Ehrich M, Brazil DP, Crean JK, Murphy M, Sadlier DM, Martin F, Godson C, McKnight AJ, van den Boom D, Maxwell AP, Savage DA (2009) Comparative analysis of DNA methylation profiles in peripheral blood leukocytes versus lymphoblastoid cell lines. Epigenetics 4(3):159–164CrossRefGoogle Scholar
  8. Brennan EP, Ehrich M, O’Donovan H, Brazil DP, Crean JK, Murphy M, Sadlier DM, Martin F, Godson C, van den Boom D, Maxwell AP, Savage DA (2010) DNA methylation profiling in cell models of diabetic nephropathy. Epigenetics 5(5):396–401CrossRefGoogle Scholar
  9. Brismar K, Fernqvist-Forbes E, Wahren J, Hall K (1994) Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 79(3):872–878PubMedGoogle Scholar
  10. Caramori ML, Kim Y, Goldfine AB, Moore JH, Rich SS, Mychaleckyj JC, Kirkpatrick D, Nickerson H, Krolewski AS, Mauer M (2015) Differential gene expression in diabetic nephropathy in individuals with type 1 diabetes. J Clin Endocrinol Metab 100(6):E876–E882CrossRefGoogle Scholar
  11. Cauchi S, Del Guerra S, Choquet H, D’Aleo V, Groves CJ, Lupi R, McCarthy MI, Froguel P, Marchetti P (2010) Meta-analysis and functional effects of the SLC30A8 rs13266634 polymorphism on isolated human pancreatic islets. Mol Genet Metab 100(1):77–82CrossRefGoogle Scholar
  12. Chan JC, Zhang Y, Ning G (2014) Diabetes in China: a societal solution for a personal challenge. Lancet Diabetes Endocrinol 2(12):969–979CrossRefGoogle Scholar
  13. Chen J, Guo Y, Zeng W, Huang L, Pang Q, Nie L, Mu J, Yuan F, Feng B (2014) ER stress triggers MCP-1 expression through SET7/9-induced histone methylation in the kidneys of db/db mice. Am J Physiol Ren Physiol 306(8):F916–F925CrossRefGoogle Scholar
  14. Chiang JL, Haller MJ, Schatz DA (2012) Update on global intervention studies in type 1 diabetes. Endocrinol Metab Clin N Am 41(4):695–712CrossRefGoogle Scholar
  15. Chimienti F, Devergnas S, Favier A, Seve M (2004) Identification and cloning of a beta-cell specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53(9):2330–2337CrossRefGoogle Scholar
  16. Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25(10):1010–1022CrossRefGoogle Scholar
  17. Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aïssi D, Wahl S, Meduri E, Morange PE, Gagnon F, Grallert H, Waldenberger M, Peters A, Erdmann J, Hengstenberg C, Cambien F, Goodall AH, Ouwehand WH, Schunkert H, Thompson JR, Spector TD, Gieger C, Trégouët DA, Deloukas P, Samani NJ (2014) DNA methylation and body-mass index: a genome-wide analysis. Lancet 383(9933):1990–8Google Scholar
  18. Dousdampanis P, Trigka K, Mouzaki A (2016) Tregs and kidney: from diabetic nephropathy to renal transplantation. World J Transplant 6(3):556–563.  https://doi.org/10.5500/wjt.v6.i3.556CrossRefPubMedPubMedCentralGoogle Scholar
  19. Falahi F, Sgro A, Blancafort P (2015) Epigenome engineering in cancer: fairytale or a realistic path to the clinic? Front Oncol 5:22.  https://doi.org/10.3389/fonc.2015.00022CrossRefPubMedPubMedCentralGoogle Scholar
  20. Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsén T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jørgensen T, Jørgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segrè AV, Skärstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, MI MC, Njølstad PR, Pedersen O, Go-T2D Consortium, T2D-GENES Consortium, Groop L, Cox DR, Stefansson K, Altshuler D (2014) Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46(4):357–363CrossRefGoogle Scholar
  21. Fradin D, Le Fur S, Mille C, Naoui N, Groves C, Zelenika D, McCarthy MI, Lathrop M, Bougnères P (2012) Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes. PLoS One 7(5):e36278CrossRefGoogle Scholar
  22. Fu Y, Tian W, Pratt EB, Dirling LB, Shyng SL, Meshul CK, Cohen DM (2009) Down-regulation of ZnT8 expression in INS-1 rat pancreatic beta cells reduces insulin content and glucose-inducible insulin secretion. PLoS One 4(5):e5679CrossRefGoogle Scholar
  23. Gnudi L, Coward RJ, Long DA (2016) Diabetic nephropathy: perspective on novel molecular mechanisms. Trends Endocrinol Metab. pii: S1043-2760(16)30074–1Google Scholar
  24. Gokulakrishnan K, Velmurugan K, Ganesan S, Mohan V (2012) Circulating levels of insulin-like growth factor binding protein-1 in relation to insulin resistance, type 2 diabetes mellitus, and metabolic syndrome (Chennai Urban Rural Epidemiology Study 118). Metabolism 61(1):43–46CrossRefGoogle Scholar
  25. Gu HF (2014) Genetic and epigenetic studies of type 1 diabetes. In: Pearce Z (ed) Type 1 diabetes: causes, treatment and potential complications. Nova, New York, USA pp 1–24Google Scholar
  26. Gu HF (2016) Genetic, epigenetic and biological effects of zinc transporter (SLC30A8) in type 1 and type 2 diabetes. Curr Diabetes Rev 12:1–9Google Scholar
  27. Gu HF, Brismar K (2012) Genetic association studies in diabetic nephropathy. Curr Diabetes Rev 8(5):336–344CrossRefGoogle Scholar
  28. Gu T, Gu HF, Hilding A, Sjöholm LK, Ostenson CG, Ekström TJ, Brismar K (2013) Increased DNA methylation levels of the insulin-like growth factor binding protein 1 gene are associated with type 2 diabetes in Swedish men. Clin Epigenetics 5(1):21.  https://doi.org/10.1186/1868-7083-5-21CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gu T, Falhammar H, Gu HF, Brismar K (2014) Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy. Clin Epigenetics 6(1):10.  https://doi.org/10.1186/1868-7083-6-10CrossRefPubMedPubMedCentralGoogle Scholar
  30. Haller-Kikkatalo K, Pruul K, Kisand K, Nemvalts V, Reimand K, Uibo R (2015) GADA and anti-ZnT8 complicate the outcome of phenotypic type 2 diabetes of adults. Eur J Clin Investig 45(3):255–262CrossRefGoogle Scholar
  31. Hayashi K, Sasamura H, Nakamura M, Azegami T, Oguchi H, Sakamaki Y, Itoh H (2014) KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J Clin Invest 124(6):2523–2537CrossRefGoogle Scholar
  32. Hong Y, Brismar K, Hall K, Pedersen NL, de Faire U (1997) Associations between insulin-like growth factor-I (IGF-I), IGF-binding protein-1, insulin and other metabolic measures after controlling for genetic influences: results from middle-aged and elderly monozygotic twins. J Endocrinol 153(2):251–257CrossRefGoogle Scholar
  33. International Diabetes Federation (2015) IDF diabetes atlas, 7th edn. (http://www.diabetesatlas.org/resources/2015-atlas.html)
  34. Jha JC, Jandeleit-Dahm KA, Cooper ME (2014) New insights into the use of biomarkers of diabetic nephropathy. Adv Chronic Kidney Dis 21(3):318–326CrossRefGoogle Scholar
  35. Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13(7):484–492CrossRefGoogle Scholar
  36. Kanoni S, Nettleton JA, Hivert MF, Ye Z, van Rooij FJ, Shungin D, Sonestedt E, Ngwa JS, Wojczynski MK, Lemaitre RN, Gustafsson S, Anderson JS, Tanaka T, Hindy G, Saylor G, Renstrom F, Bennett AJ, van Duijn CM, Florez JC, Fox CS, Hofman A, Hoogeveen RC, Houston DK, Hu FB, Jacques PF, Johansson I, Lind L, Liu Y, McKeown N, Ordovas J, Pankow JS, Sijbrands EJ, Syvänen AC, Uitterlinden AG, Yannakoulia M, Zillikens MC, MAGIC Investigators, Wareham NJ, Prokopenko I, Bandinelli S, Forouhi NG, Cupples LA, Loos RJ, Hallmans G, Dupuis J, Langenberg C, Ferrucci L, Kritchevsky SB, MI MC, Ingelsson E, Borecki IB, Witteman JC, Orho-Melander M, Siscovick DS, Meigs JB, Franks PW, Dedoussis GV (2011) Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. Diabetes 60(9):2407–2416CrossRefGoogle Scholar
  37. Kato M, Natarajan R (2014) Diabetic nephropathy – emerging epigenetic mechanisms. Nat Rev Nephrol 10(9):517–530CrossRefGoogle Scholar
  38. Korabecna M, Pazourkova E, Horinek A, Mokrejsova M, Tesar V (2013) Methylation status of immune response genes promoters in cell-free DNA differs in hemodialyzed patients with diabetic nephropathy according to the intensity of anemia therapy. Blood Purif 36(3–4):280–286CrossRefGoogle Scholar
  39. Lee PD, Giudice LC, Conover CA, Powell DR (1997) Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med 216(3):319–357CrossRefGoogle Scholar
  40. Lewitt MS, Hilding A, Ostenson CG, Efendic S, Brismar K, Hall K (2008) Insulin-like growth factor-binding protein-1 in the prediction and development of type 2 diabetes in middle-aged Swedish men. Diabetologia 51(7):1135–1145CrossRefGoogle Scholar
  41. Lewitt MS, Hilding A, Brismar K, Efendic S, Ostenson CG, Hall K (2010) IGF-binding protein 1 and abdominal obesity in the development of type 2 diabetes in women. Eur J Endocrinol 163(2):233–242CrossRefGoogle Scholar
  42. Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T, Berglund G, Altshuler D, Nilsson P, Groop L (2008) Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 359(21):2220–2232CrossRefGoogle Scholar
  43. Mohamud WN, Ismail AA, Sharifuddin A, Ismail IS, Musa KI, Kadir KA, Kamaruddin NA, Yaacob NA, Mustafa N, Ali O, Harnida S, Bebakar WM (2011) Prevalence of metabolic syndrome and its risk factors in adult Malaysians: results of a nationwide survey. Diabetes Res Clin Pract 91(2):239–245CrossRefGoogle Scholar
  44. Moresco RN, Sangoi MB, De Carvalho JA, Tatsch E, Bochi GV (2013) Diabetic nephropathy: traditional to proteomic markers. Clin Chim Acta 421:17–30CrossRefGoogle Scholar
  45. Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C (2016) Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev.  https://doi.org/10.1002/dmrr.2841
  46. Peng R, Liu H, Peng H, Zhou J, Zha H, Chen X, Zhang L, Sun Y, Yin P, Wen L, Wu T, Zhang Z (2015) Promoter hypermethylation of let-7a-3 is relevant to its down-expression in diabetic nephropathy by targeting UHRF1. Gene 570(1):57–63CrossRefGoogle Scholar
  47. Petersson U, Ostgren CJ, Brudin L, Brismar K, Nilsson PM (2009) Low levels of insulin-like growth-factor-binding protein-1 (IGFBP-1) are prospectively associated with the incidence of type 2 diabetes and impaired glucose tolerance (IGT): the Söderåkra cardiovascular risk factor study. Diabete Metab 35(3):198–205CrossRefGoogle Scholar
  48. Pierce M, Keen H, Bradley C (1995) Risk of diabetes in offspring of parents with non-insulin-dependent diabetes. Diabet Med 12(1):6–13CrossRefGoogle Scholar
  49. Rajpathak SN, Gunter MJ, Wylie-Rosett J, Ho GY, Kaplan RC, Muzumdar R, Rohan TE, Strickler HD (2009) The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes Metab Res Rev 25(1):3–12CrossRefGoogle Scholar
  50. Reddy MA, Sumanth P, Lanting L, Yuan H, Wang M, Mar D, Alpers CE, Bomsztyk K, Natarajan R (2014) Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 85(2):362–73Google Scholar
  51. Sapienza C, Lee J, Powell J, Erinle O, Yafai F, Reichert J, Siraj ES, Madaio M (2011) DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy. Epigenetics 6(1):20–28CrossRefGoogle Scholar
  52. Schena FP, Serino G, Sallustio F (2014) MicroRNAs in kidney diseases: new promising biomarkers for diagnosis and monitoring. Nephrol Dial Transplant 29(4):755–763CrossRefGoogle Scholar
  53. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316(5829):1341–1345CrossRefGoogle Scholar
  54. Seliger SL, Davis C, Stehman-Breen C (2001) Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 10(2):219–225CrossRefGoogle Scholar
  55. Seman NA, Mohamud WN, Östenson CG, Brismar K, Gu HF (2015) Increased DNA methylation of the SLC30A8 gene promoter is associated with type 2 diabetes in a Malay population. Clin Epigenetics 7:30.  https://doi.org/10.1186/s13148-015-0049-5CrossRefPubMedPubMedCentralGoogle Scholar
  56. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445(7130):881–885CrossRefGoogle Scholar
  57. Starkey JM, Tilton RG (2012) Proteomics and systems biology for understanding diabetic nephropathy. J Cardiovasc Transl Res 5(4):479–490.  https://doi.org/10.1007/s12265-012-9372-9CrossRefPubMedPubMedCentralGoogle Scholar
  58. Steffes MW, Sutherland DE, Goetz FC, Rich SS, Mauer SM (1985) Studies of kidney and muscle biopsy specimens from identical twins discordant for type I diabetes mellitus. N Engl J Med 312(20):1282–1287CrossRefGoogle Scholar
  59. Suikkari AM, Koivisto VA, Koistinen R, Seppälä M, Yki-Järvinen H (1989) Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin. J Clin Endocrinol Metab 68(1):135–140CrossRefGoogle Scholar
  60. Sun G, Reddy MA, Yuan H, Lanting L, Kato M, Natarajan R (2010) Epigenetic histone methylation modulates fibrotic gene expression. J Am Soc Nephrol 21(12):2069–80Google Scholar
  61. Swan EJ, Maxwell AP, McKnight AJ (2015) Distinct methylation patterns in genes that affect mitochondrial function are associated with kidney disease in blood-derived DNA from individuals with type 1 diabetes. Diabet Med 32(8):1110–1115CrossRefGoogle Scholar
  62. Tamaki M, Fujitani Y, Uchida T, Hirose T, Kawamori R, Watada H (2009) Down-regulation of ZnT8 expression in pancreatic β-cells of diabetic mice. Islets 1(2):124–128CrossRefGoogle Scholar
  63. Tamayo T, Rosenbauer J, Wild SH, Spijkerman AM, Baan C, Forouhi NG, Herder C, Rathmann W (2014) Diabetes in Europe: an update. Diabetes Res Clin Pract 103(2):206–217CrossRefGoogle Scholar
  64. Thomas MC (2016) Epigenetic mechanisms in diabetic kidney disease. Curr Diab Rep 16(3):31.  https://doi.org/10.1007/s11892-016-0723-9CrossRefPubMedGoogle Scholar
  65. VanderJagt TA, Neugebauer MH, Morgan M, Bowden DW, Shah VO (2015) Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy. World J Diabetes 6(9):1113–1121CrossRefGoogle Scholar
  66. Villeneuve LM, Natarajan R (2010) The role of epigenetics in the pathology of diabetic complications. Am J Physiol Ren Physiol 299(1):F14–F25CrossRefGoogle Scholar
  67. Yuan H, Reddy MA, Deshpande S, Jia Y, Park JT, Lanting LL, Jin W, Kato M, Xu ZG, Das S, Natarajan R (2016) Epigenetic histone modifications involved in Profibrotic Gene regulation by 12/15-lipoxygenase and its oxidized lipid products in diabetic nephropathy. Antioxid Redox Signal 24(7):361–375CrossRefGoogle Scholar
  68. Zhang H, Cai X, Yi B, Huang J, Wang J, Sun J (2014) Correlation of CTGF gene promoter methylation with CTGF expression in type 2 diabetes mellitus with or without nephropathy. Mol Med Rep 9(6):2138–2144CrossRefGoogle Scholar
  69. Zhang H, Li A, Zhang W, Huang Z, Wang J, Yi B (2016) High glucose-induced cytoplasmic translocation of Dnmt3a contributes to CTGF hypo-methylation in mesangial cells. Biosci Rep 36(4). pii: e00362.  https://doi.org/10.1042/BSR20160141
  70. Zhou TB, Drummen GP, Jiang ZP, Li HY (2015) Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus. Ren Fail 37(8):1247–1259CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical Science, Intervention and TechnologiesKarolinska Institutet, Karolinska University HospitalStockholmSweden
  2. 2.Center for Molecular MedicineKarolinska Institutet, Karolinska University HospitalStockholmSweden

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