Generic placeholder image

Current Diabetes Reviews


ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Research Article

MTHFR Polymorphisms and Cardiac Parameters in Patients with Diabetic Retinopathy

Author(s): João Otávio Scarano Alcântara*, Caroline Severo de Assis, Tainá Gomes Diniz, Vanessa Polyana de Sousa Brito, Yohanna de Oliveira, Alexandre Sérgio Silva, Isabella Wanderley de Queiroga Evangelista, Fagner Dayan de Lima Gomes, Enéas Ricardo de Morais Gomes, Valério Marcelo Vasconcelos do Nascimento, Rafaela Lira Formiga Cavalcanti de Lima and Darlene Camati Persuhn

Volume 19, Issue 3, 2023

Published on: 10 August, 2022

Article ID: e250522205236 Pages: 9

DOI: 10.2174/1573399818666220525103323

Price: $65


Background: Diabetes Mellitus (DM) is directly associated with cardiovascular dysfunctions and microvascular complications, such as diabetic retinopathy (DR). The association between DR and increased risks of developing cardiovascular diseases has been described. The low activity of the Methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the metabolism of homocysteine, can lead to hyperhomocysteinemia that has already been related to cardiac outcomes and resistance to insulin. The A1298C and C677T polymorphisms in the MTHFR can reduce enzyme activity.

Objective: The study aims to analyze the association between MTHFR genotypes and cardiac parameters in patients with DR.

Methods: DM patients diagnosed with DR (n=65) were categorized and compared according to MTHFR genotypes A1298C (AA and AC+CC groups) and C677T (CC and CT+TT) groups; biochemical, cardiological, anthropometric, genetic, lifestyle and vitamin B9 and B12 consumption variables. Fischer's exact test and Poisson regression were performed to assess the relationship between variables.

Results: Comparing echocardiographic and electrocardiogram parameters within genotypic groups, we found a significant association between left atrial dilation and C677T polymorphism. Left atrium diameter was higher in the T allele carriers (CT+TT group), with a prevalence ratio of 0.912. This association was confirmed in the regression model, including confounding variables. The other cardiac structural and functional parameters studied were not significantly associated with the A1298C or C677T genotypes.

Conclusion: The MTHFR C677T genotype may contribute to atrial remodeling in RD patients. We found an association between the diameter of the left atrium and the T allele of the MTHFR C677T polymorphism in patients with DR.

Keywords: Diabetes, diabetic retinopathy, MTHFR, left atrium, polymorphisms, cardiovascular system.

Brutti A, Flores J, Hermes J, et al. Diabetes Mellitus: Definition, diagnosis, treatment and mortality in Brazil, Rio Grande do Sul and Santa Maria, from 2010 to 2014. Braz J Hea Rev 2019; 2(4): 3174-82.
Quinaglia T, Oliveira DC, Matos-Souza JR, Sposito AC. Diabetic cardiomyopathy: Factual or factoid? Rev Assoc Med Bras 2019; 65(1): 61-9.
[] [PMID: 30758422]
Khalil H. Diabetes microvascular complications-A clinical update. Diabetes Metab Syndr 2017; 11(1) (Suppl. 1): S133-9.
[] [PMID: 27993541]
McVicar CM, Ward M, Colhoun LM, et al. Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice. Diabetologia 2015; 58(5): 1129-37.
[] [PMID: 25687235]
Menezes M, Lopes C, Nogueira L. Impact of educational interventions in reducing diabetic complications: A systematic review. Rev Bras Enferm 2016; 69(4): 773-84.
[] [PMID: 27508485]
Shoeibi N, Bonakdaran S. Is there any correlation between diabetic retinopathy and risk of cardiovascular disease? Curr Diabetes Rev 2017; 13(1): 81-6.
[] [PMID: 26456361]
Almeida F, Esteves J, Gross J, et al. Severe forms of retinopathy predict the presence of subclinical atherosclerosis in type 1 diabetes subjects. Arq Bras Cardiol 2011; 97(4): 346-9.
[] [PMID: 22011803]
Xie J, Ikram MK, Cotch MF, et al. Association of diabetic macular edema and proliferative diabetic retinopathy with cardiovascular disease: A systematic review and meta-analysis. JAMA Ophthalmol 2017; 135(6): 586-93.
[] [PMID: 28472362]
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111-3.
[] [PMID: 7647779]
Kowluru RA. Faulty homocysteine recycling in diabetic retinopathy. Eye Vis (Lond) 2020; 7: 4.
Dos Santos Nunes MK, Silva AS, de Queiroga Evangelista IW, et al. Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators. Diabetol Metab Syndr 2017; 9(9): 84.
[] [PMID: 29075332]
Maeda M, Yamamoto I, Fukuda M, et al. MTHFR gene polymorphism is susceptible to diabetic retinopathy but not to diabetic nephropathy in Japanese type 2 diabetic patients. J Diabetes Complications 2008; 22(2): 119-25.
[] [PMID: 18280442]
Maeda M, Fujio Y, Azuma J. MTHFR gene polymorphism and diabetic retinopathy. Curr Diabetes Rev 2006; 2(4): 467-76.
[] [PMID: 18220649]
Xu WH, Zhuang Y, Han X, Yuan ZL. Methylenetetrahydrofolate reductase C677T polymorphism and diabetic retinopathy risk: A meta-analysis of the Chinese population. J Int Med Res 2020; 48(1)300060518816834
[] [PMID: 30628508]
Yildirim A, Akalin I, Nuhoglu I, Akbas E, Turk A. MTHFR (677C>T) gene polymorphism increase the risk of proliferative retinopathy in type 2 diabetes. Int J Sci Res Innovat Technol 2019; 6(9): 21-32.
Yigit S, Karakus N, Inanir A. Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Mol Vis 2013; 19: 1626-30.
[PMID: 23901246]
Solarz DE, Maddukuri P, Aligeti V, Aragam J. Homocysteine levels correlate with left atrial size and clinical outcomes in systolic heart failure. J Card Fail 2007; 13(6): 99-100.
Angelo L, Vieira M, Rodrigues S, et al. Echocardiographic reference values in a sample of asymptomatic adult Brazilian population. Arq Bras Cardiol 2007; 89(3): 184-90.
[] [PMID: 17906818]
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18(6): 499-502.
[] [PMID: 4337382]
Brazilian Diabetes Society. Guidelines of the Brazilian diabetes society. Brazil 2019.
Precoma DB, de Oliveira GMM, Simao AF, et al. Updated Cardiovascular Prevention Guideline of the Brazilian Society of Cardiology – 2019. Arq Bras Cardiol 2019; 113(4): 787-891.
[PMID: 31691761]
Sposito AC, Caramelli B, Fonseca FAH, et al. IV Brazilian Guideline for Dyslipidemia and Atherosclerosis prevention: Department of Atherosclerosis of Brazilian Society of Cardiology. Arq Bras Cardiol 2007; 88(1): 2-19.
Brazilian Society of Nephrology. Biomarkers in Nephrology [Internet]. Brazil 2011. Available from: (Accessed on: 2021 Feb 5).
World Health Organization. Obesity: Preventing and Managing the Global Epidemic Report on a WHO Consultation (WHO Technical Report Series 894) 2000. Available from:
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16(3): 1215.
[] [PMID: 3344216]
van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet 1998; 62(5): 1044-51.
[] [PMID: 9545395]
Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: Incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 2001; 47(4): 661-6.
[] [PMID: 11274015]
Vannucchi H, Melo SS. Hyperhomocysteinemia and cardiometabolic risk. Arq Bras Endocrinol Metabol 2009; 53(5): 540-9.
[] [PMID: 19768245]
Fisberg RM, Marchioni DM, Colucci AC. Assessment of food consumption and nutrient intake in clinical practice. Arq Bras Endocrinol Metabol 2009; 53(5): 617-24.
[] [PMID: 19768252]
Dietary Reference Intakes. Applications in Dietary Assessment. Washington, DC: Institute of Medicine 2000.
Hoit BD. Left atrial size and function: Role in prognosis. J Am Coll Cardiol 2014; 63(6): 493-505.
[] [PMID: 24291276]
Bouzas-Mosquera A, Broullón FJ, Álvarez-García N, et al. Left atrial size and risk for all-cause mortality and ischemic stroke. CMAJ 2011; 183(10): E657-64.
[] [PMID: 21609990]
Karagöz A, Bezgin T, Kutlutürk I, et al. Subclinical left ventricular systolic dysfunction in diabetic patients and its association with retinopathy: A 2D speckle tracking echocardiography study. Herz 2015; 40(3) (Suppl. 3): 240-6.
[] [PMID: 25205476]
Aguilar D, Hallman DM, Piller LB, et al. Adverse association between diabetic retinopathy and cardiac structure and function. Am Heart J 2009; 157(3): 563-8.
[] [PMID: 19249430]
Kluijtmans LA, van den Heuvel LP, Boers GH, et al. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58(1): 35-41.
[PMID: 8554066]
Kluijtmans LAJ, Kastelein JJP, Lindemans J, et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1997; 96(8): 2573-7.
[] [PMID: 9355896]
Marcucci R, Betti I, Cecchi E, et al. Hyperhomocysteinemia and vitamin B6 deficiency: New risk markers for nonvalvular atrial fibrillation? Am Heart J 2004; 148(3): 456-61.
[] [PMID: 15389232]
Shimano M, Inden Y, Tsuji Y, et al. Circulating homocysteine levels in patients with radiofrequency catheter ablation for atrial fibrillation. Europace 2008; 10(8): 961-6.
[] [PMID: 18550508]
Guéant Rodriguez RM, Spada R, Pooya S, et al. Homocysteine predicts increased NT-pro-BNP through impaired fatty acid oxidation. Int J Cardiol 2013; 167(3): 768-75.
[] [PMID: 22459404]
Kim YH, Lim DS, Lee JH, et al. Gene expression profiling of oxidative stress on atrial fibrillation in humans. Exp Mol Med 2003; 35(5): 336-49.
[] [PMID: 14646586]
Lin PH, Lee SH, Su CP, Wei YH. Oxidative damage to mitochondrial DNA in atrial muscle of patients with atrial fibrillation. Free Radic Biol Med 2003; 35(10): 1310-8.
[] [PMID: 14607530]
Sun X, Li X, Liang G, Yu J. Correlation between serum homocysteine, Galectin-3 concentration and atrial structural remodeling in atrial fibrillation patients. Pteridines 2020; 31(1): 83-90.
Tawfik A, Mohamed R, Elsherbiny NM, DeAngelis MM, Bartoli M, Al-Shabrawey M. Homocysteine: A potential biomarker for diabetic retinopathy. J Clin Med 2019; 8(1): 121.
[] [PMID: 30669482]
Ibrahim AS, Mander S, Hussein KA, et al. Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration. Oncotarget 2016; 7(8): 8532-45.
[] [PMID: 26885895]
Tawfik A, Samra YA, Elsherbiny NM, Al-Shabrawey M. Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction. Biomolecules 2020; 10(8): 1119.
[] [PMID: 32751132]
Chait A, Malinow MR, Nevin DN, et al. Increased dietary micronutrients decrease serum homocysteine concentrations in patients at high risk of cardiovascular disease. Am J Clin Nutr 1999; 70(5): 881-7.
[] [PMID: 10539749]
Brouwer IA, van Dusseldorp M, West CE, et al. Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr 1999; 129(6): 1135-9.
[] [PMID: 10356077]
Jacob RA, Wu MM, Henning SM, Swendseid ME. Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. J Nutr 1994; 124(7): 1072-80.
[] [PMID: 8027858]
Chasan-Taber L, Selhub J, Rosenberg IH, et al. A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. J Am Coll Nutr 1996; 15(2): 136-43.
[] [PMID: 8778142]
Van Wagoner DR. Is homocysteine a mediator of atrial dysfunction or just another marker of endothelial dysfunction? Europace 2008; 10(8): 899-900.
[] [PMID: 18593699]
Giusti B, Gori AM, Marcucci R, et al. Role of C677T and A1298C MTHFR, A2756G MTR and -786 C/T eNOS gene polymorphisms in atrial fibrillation susceptibility. PLoS One 2007; 2(6)e495
[] [PMID: 17551576]
Mesquita ET, Jorge AJL. Heart failure with normal ejection fraction: New diagnostic criteria and pathophysiological advances. Arq Bras Cardiol 2009; 93(2): 180-7.
[] [PMID: 19838497]
Cheung N, Wang JJ, Rogers SL, et al. Diabetic retinopathy and risk of heart failure. J Am Coll Cardiol 2008; 51(16): 1573-8.
[] [PMID: 18420100]
Mancuso FJN, Moisés VA, Almeida DR, et al. Left atrial volume determinants in patients with non-ischemic dilated cardiomyopathy. Arq Bras Cardiol 2015; 105(1): 65-70.
[PMID: 25993483]
Acarturk E, Koc M, Bozkurt A, Unal I. Left atrial size may predict exercise capacity and cardiovascular events in patients with heart failure. Tex Heart Inst J 2008; 35(2): 136-43.
[PMID: 18612491]
Fitipaldi H, McCarthy MI, Florez JC, Franks PW. A global overview of precision medicine in type 2 diabetes. Diabetes 2018; 67(10): 1911-22.
[] [PMID: 30237159]
Fradkin JE, Hanlon MC, Rodgers GP. NIH precision medicine initiative: Implications for diabetes research. Diabetes Care 2016; 39(7): 1080-4.
[] [PMID: 27289128]
Groop L. New approaches beyond genetics: Towards precision medicine in diabetes. Diabetologia 2016; 59(12): 2495-6.
[] [PMID: 27722776]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy