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Open Access 01-12-2017 | Research

Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators

Authors: Mayara Karla dos Santos Nunes, Alexandre Sérgio Silva, Isabella Wanderley de Queiroga Evangelista, João Modesto Filho, Cecília Neta Alves Pegado Gomes, Rayner Anderson Ferreira do Nascimento, Rafaella Cristhine Pordeus Luna, Maria José de Carvalho Costa, Naila Francis Paulo de Oliveira, Darlene Camati Persuhn

Published in: Diabetology & Metabolic Syndrome | Issue 1/2017

Abstract

Background

DNA methylation is an epigenetic mechanism for regulating the transcription of many genes and has been linked to the development of various diseases. A promising gene to investigate is methylenetetrahydrofolate reductase (MTHFR), since the enzyme methylenetetrahydrofolate reductase (MTHFR) promotes methyl radical synthesis in the homocysteine cycle and can provide methyl groups for DNA methylation. In addition, several studies have correlated gene polymorphisms of this enzyme with a greater risk of diabetes, but little is known regarding the relationship between epigenetic changes in this gene and diabetes and its complications. The aim of this study was to investigate the relationship between methylation profile in the MTHFR gene promoter and biochemical, inflammatory and oxidative stress markers in individuals with type 2 diabetes (T2DM) who have been diagnosed for 5–10 years with or without diabetic retinopathy (DR) and nephropathy (DN).

Methods

Specific PCR for methylation (MSP) was used to analyze MTHFR methylation profile in leucocytes DNA. Biochemical markers (glycemia, glycated hemoglobin, total cholesterol, LDL, HDL, triglycerides, serum creatinine), inflammatory markers (C-reactive protein and alpha-1 acid glycoprotein) and oxidative stress (total antioxidant and malonaldehyde) were determined in peripheric blood samples and microalbuminuria in 24 h urine samples. The X² and Mann–Whitney statistical tests were performed and p < 0.05 were considered significant.

Results

The hypermethylated profile was most frequently observed in individuals with retinopathy (p < 0.01) and was associated with higher total cholesterol and LDL levels (p = 0.0046, 0.0267, respectively). Individuals with DN and hypermethylated profiles had higher levels of alpha-1 acid glycoprotein (p = 0.0080) and total antioxidant capacity (p = 0.0169) compared to subjects without complications.

Conclusions

Hypermethylation in the promoter of the MTHFR gene is associated with the occurrence of DR and with biochemical, inflammatory and oxidative stress parameters in the context of chronic complications

Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68. doi:10.1038/nbt.1685.CrossRefPubMed

Narayanan N, Tyagi N, Shah A, Pagni S, Tyagi SC. Hyperhomocysteinemia during aortic aneurysm, a plausible role of epigenetics. Int J Physiol Pathophysiol Pharmacol. 2013;5:32–42. doi:10.1096/fj.14-250183.PubMedPubMedCentral

Real JT, Folgado J, Molina Mendez M, Martinez-Hervás S, Peiro M, Ascaso JF. Plasma homocysteine, Lp (a), and oxidative stress markers in peripheral macroangiopathy in patients with type 2 diabetes mellitus. Clin Investig Arterioscler. 2016;28(4):188–94. doi:10.1016/j.arteri.2016.05.007.CrossRefPubMed

Bradshaw G, Sutherland HG, Camilleri ET, Lea RA, Haupt LM, Lyn RG. Genetic and epigenetic variants in the MTHFR gene are not associated with non-Hodgkin lymphoma. Meta Gene. 2015;6:91–5. doi:10.1016/j.mgene.2015.09.004.CrossRefPubMedPubMedCentral

Liew S-C, Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015;58:1–10. doi:10.1016/j.ejmg.2014.10.004.CrossRefPubMed

Herman WH. The global burden of diabetes: an overview. In: Dagogo-Jack S, editor. Diabetes mellitus in developing countries and underserved communities. Berlin: Springer International Publishing; 2017. p. 1–5.

World Health Organization. Global report on diabetes. Geneva: World Health Organization; 2016. http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf. Accessed 20 Nov 2016.

Abbas S, Raza ST, Ahmed F, Ahmad A, Rizvi S, Mahdi F. Association of Genetic polymorphism of PPARγ-2, ACE, MTHFR, FABP-2 and FTO genes in risk prediction of type 2 diabetes mellitus. J Biomed Sci. 2013;20(1):80. doi:10.1186/1423-0127-20-80.CrossRefPubMedPubMedCentral

El Hajj Chehadeh SW, Jelinek HF, Al Mahmeed WA, Tay GK, Odama UO, Elghazali GE, Al Safar HS. Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population. Meta Gene. 2016;9:70–5. doi:10.1016/j.mgene.2016.04.002.CrossRefPubMedPubMedCentral

10.

Liu CC, Ho WY, Leu KL, Tsai HM, Yang TH. Effects of S-adenosylhomocysteine and homocysteine on DNA damage and cell cytotoxicity in murine hepatic and microglia cell lines. J Biochem Mol Toxicol. 2009;23(5):349–56. doi:10.1002/jbt.20298.CrossRefPubMed

11.

Schalinske KL, Smazal AL. Homocysteine imbalance: a pathological metabolic marker. Adv Nutr. 2012;3:755–62. doi:10.3945/an.112.002758.CrossRefPubMedPubMedCentral

12.

Zheng J, Cheng J, Zhang Q, Xiao X. Novel insights into DNA methylation and its critical implications in diabetic vascular complications. Biosci Rep. 2017. doi:10.1042/BSR20160611.

13.

Chambers JC, Loh M, Lehne B, Drong A, Kriebel J, Motta V, et al. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study. Lancet Diabetes Endocrinol. 2015;3(7):526–34. doi:10.1016/S2213-8587(15)00127-8.CrossRefPubMedPubMedCentral

14.

Kulkarni H, Kos MZ, Neary J, Dyer TD, Kent JW Jr, Göring HH, et al. Novel epigenetic determinants of type 2 diabetes in Mexican-American families. Hum Mol Genet. 2015;24(18):5330–44. doi:10.1093/hmg/ddv232.CrossRefPubMedPubMedCentral

15.

Florath I, Butterbach K, Heiss J, Bewerunge-Hudler M, Zhang Y, Schöttker B. Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults. Diabetologia. 2016;59(1):130–8. doi:10.1007/s00125-015-3773-7.CrossRefPubMed

16.

Soriano-Tárraga C, Jiménez-Conde J, Giralt-Steinhauer E, Mola-Caminal M, Vivanco-Hidalgo RM, Ois A, et al. Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia. Hum Mol Genet. 2016;25(3):609–19. doi:10.1093/hmg/ddv493.CrossRefPubMed

17.

Elliott HR, Shihab HA, Lockett GA, Holloway JW, Mcrae AF, Smith GD, Ring SM, Gaunt TR, Relton CL. The role of DNA methylation in type 2 diabetes aetiology—using genotype as a causal anchor. Diabetes. 2017;66(6):1713–22. doi:10.2337/db16-0874.CrossRefPubMed

18.

Ozdemir O, Silan F, Urfali M, Uludag A, Ari E, Kayatas M. Variable R. Msp1 fragmentation in genomic DNA due to DNA hypomethylation in CRF patients with MTHFR C677Tgene polymorphism: from genetics to epigenetics. Gene Ther. Mol Biol. 2014;16:77–87.

19.

Yang XH, Cao RF, Yu Y, Sui M, Zhang T, Xu JY, Wang XM. A study on the correlation between MTHFR promoter methylation and diabetic nephropathy. Am J Transl Res. 2016;8(11):4960–7.PubMedPubMedCentral

20.

Wei K, Sutherland H, Camilleri E, Haupt LM, Griffiths LR, Gan SH. Computational epigenetic profiling of CpG islets in MTHFR. Mol Biol Rep. 2014;41(12):8285–92. doi:10.1007/s11033-014-3729-x.CrossRefPubMed

21.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351–8.CrossRefPubMed

22.

Brand-Williams W, Cuvelier M-E, Berset C. Use of a free radical method to evaluate antioxidant activity. LWT Food Sci Technol. 1995;28:25–30.CrossRef

23.

Miller Wer SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.CrossRef

24.

Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996;93(18):9821–6.CrossRefPubMedPubMedCentral

25.

Khazamipour N, Noruzinia M, Fatehmanesh P, Keyhanee M, Pujol P. MTHFR promoter hypermethylation in testicular biopsies of patients with non-obstructive azoospermia: the role of epigenetics in male infertility. Hum Reprod. 2009;24(9):2361–4. doi:10.1093/humrep/dep194.CrossRefPubMed

26.

Tschiedel B. Complicações crônicas do diabetes. JBM. 2014;102(5):7–12.

27.

Isaacs AN, Vincen A. Antihypertensive therapy for the prevention of nephropathy in diabetic hypertensive patients. J Clin Pharm Ther. 2016;41(2):111–5. doi:10.1111/jcpt.12361.CrossRefPubMed

28.

Sacks FM, Hermans MP, Fioretto P, Valensi P, Davis T, Horton E, et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation. 2014;129(9):999–1008. doi:10.1161/CIRCULATIONAHA.113.002529.CrossRefPubMed

29.

Frank RN. Diabetic retinopathy and systemic factors. Middle East Afr J Ophthalmol. 2015;22(2):151–6. doi:10.4103/0974-9233.154388.CrossRefPubMedPubMedCentral

30.

Chen YH, Chen HS, Tarng DC. More impacto of microalbumiburia on retinopathy than moderately reduce GFR among type 2 diabetic patients. Diabetes Care. 2012;35:803–8.CrossRefPubMedPubMedCentral

31.

Man RE, Sasongko MB, Wang JJ, Macisaac R, Wong TY, Sabanayagam C, Lamoureux EL. The association of estimated glomerular filtration rate with diabetic retinopathy and macular edema renal function and diabetic eye disease. Invest Ophthalmol Vis Sci. 2015;56(8):4810–6. doi:10.1167/iovs.15-16987.CrossRefPubMed

32.

Abougalambou SS, Abougalambou AS. Risk factors associated with diabetic retinopathy among type 2 diabetes patients at teaching hospital in Malaysia. Diabetes Metab Syndr. 2015;9(2):98–103. doi:10.1016/j.dsx.2014.04.019.CrossRefPubMed

33.

Silva D, Pais de Lacerda A. High-sensitivity C-reactive protein as a biomarker of risk in coronary artery disease. Rev Port Cardiol. 2012;31(11):733–45. doi:10.1016/j.repc.2012.02.018.PubMed

34.

Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D, Juenger C, Schnabel RB, Abt TG, Laskowski R, Wiltink J, Schulz E, Blankenberg S, Lackner KJ, Münzel T, Wild PS. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care. 2015;38(7):1356–64. doi:10.2337/dc14-3008.CrossRefPubMed

35.

Sem D, Ghosh S, Roy D. Correlation of C-reactive protein and body mass index with diabetic retinopathy in Indian population. Diabetes Metab Syndr. 2015;9:28–9. doi:10.1016/j.dsx.2014.05.004.CrossRef

36.

Yang XF, Deng Y, Gu H, Lim A, Snellingen T, Liu XP, Wang NL, Domalpally A, Danis R, Liu NP. C-reactive protein and diabetic retinopathy in Chinese patients with type 2 diabetes mellitus. Int J Ophthalmol. 2016;9(1):111–8. doi:10.18240/ijo.2016.01.19.PubMedPubMedCentral

37.

Song J, Chen S, Liu X, Duan H, Kong J, Li Z. Relationship between C-reactive protein level and diabetic retinopathy: a systematic review and meta-analysis. PLoS ONE. 2015;10(12):e0144406. doi:10.1371/journal.pone.0144406.CrossRefPubMedPubMedCentral

38.

Ghattas M, El-Shaarawy E, Mesbah N, Abo-Elmatty D. DNA methylation status of the methylenetetrahydrofolate reductase gene promoter in peripheral blood of end-stage renal disease patients. Mol Biol Rep. 2014;41:683–8. doi:10.1007/s11033-013-2906-7.CrossRefPubMed

39.

Wei LK, Sutherland H, Au A, Camilleri E, Haupt LM, Gan SH, Griffiths LR. A potential epigenetic marker mediating serum folate and vitamin B12 levels contributes to the risk of ischemic stroke. Biomed Res Int. 2015;2015:167976. doi:10.1155/2015/167976.PubMed

40.

Ge J, Wang J, Zhang F, Diao B, Song ZF, Shan LL, Wang W, Cao HJ. LI XQ. Correlation between MTHFR gene methylation and pre-eclampsia, and its clinical significance. Genet Mol Res. 2015;14:8021–8. doi:10.4238/2015.July.17.10.CrossRefPubMed

41.

Coppedè F, Denaro M, Tannorella P, Migliore L. Increased MTHFR promoter methylation in mothers of down syndrome individuals. Mutat Res. 2016;787:1–6. doi:10.1016/j.mrfmmm.2016.02.008.CrossRefPubMed

42.

Wang L, Zhang J, Wang S. Demethylation in the promoter region of MTHFR gene and its mRNA expression in cultured human vascular smooth muscle cells induced by homocysteine. Wei Sheng Yan Jiu. 2007;36:291–4.PubMed

43.

Karmin O, Lynn EG, Chung YH, Siow YL, Man RYK, Choy PC. Homocysteine stimulates the production and secretion of cholesterol in hepatic cells. Biochimica et Biophysica Acta (BBA)-Lipids and Lipid. Metabolism. 1998;1393:317–24. doi:10.1016/S0005-2760(98)00086-1.

44.

Chang YC, Wu WC. Dyslipidemia and diabetic retinopathy. Rev Diabet Stud. 2013;10:121–32. doi:10.1900/RDS.2013.10.121.CrossRefPubMedPubMedCentral

45.

Lorenzi M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res. 2007;2007:61038. doi:10.1155/2007/61038.CrossRefPubMedPubMedCentral

46.

Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endo Metab Disord. 2010;11(1):61–74. doi:10.1007/s11154-010-9134-4.CrossRef

47.

Haldar SR, Chakrabarty A, Chowdhury S, Haldar A, Sengupta S, Bhattacharyya M. Oxidative stress-related genes in type 2 diabetes: association analysis and their clinical impact. Biochem Genet. 2015;53(4–6):93–119. doi:10.1007/s10528-015-9675-z.CrossRefPubMed

48.

Fournier T, Medjoubi-N N, Porquet D. Alpha-1-acid glycoprotein. Biochim Biophys Acta. 2000;1482(1–2):157–71.CrossRefPubMed

49.

Gomes MB, Nogueira VG. Acute-phase proteins and microalbuminuria among patients with type 2 diabetes. Diabetes Res Clin Pract. 2004;66(1):31–9. doi:10.1016/j.diabres.2004.02.009.CrossRefPubMed

50.

Currie G, Mckay G, Delles C. Biomarkers in diabetic nephropathy: present and future. World J Diabetes. 2014;5(6):763–76. doi:10.4239/wjd.v5.i6.763.CrossRefPubMedPubMedCentral

Title: Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators
Authors: Mayara Karla dos Santos Nunes
Alexandre Sérgio Silva
Isabella Wanderley de Queiroga Evangelista
João Modesto Filho
Cecília Neta Alves Pegado Gomes
Rayner Anderson Ferreira do Nascimento
Rafaella Cristhine Pordeus Luna
Maria José de Carvalho Costa
Naila Francis Paulo de Oliveira
Darlene Camati Persuhn
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Diabetology & Metabolic Syndrome / Issue 1/2017
Electronic ISSN: 1758-5996
DOI: https://doi.org/10.1186/s13098-017-0284-3

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Conclusions

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