The MTHFR promoter hypermethylation pattern associated with the A1298C polymorphism influences lipid parameters and glycemic control in diabetic patients

Bezerra, Herlanny Santana; Assis, Caroline Severo de; Nunes, Mayara Karla dos Santos; Evangelista, Isabella; Filho, João Aragão Ximenes; Gomes, Cecília Neta Alves Pegado; Nascimento, Rayner Anderson Ferreira do; Luna, Rafaella Cristhine Pordeus; Costa, Maria José de Carvalho; Oliveira, Naila Francis Paulo de; Persuhn, Darlene Camati

doi:10.1186/s13098-019-0399-9

Cited by 15 publications

(17 citation statements)

References 25 publications

(32 reference statements)

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“…Increasing evidence suggests that MTHFR hypermethylation represents a risk factor for various human disorders [15,16,17,18,19,20,21,22,23,24,25,26], but little is still known concerning the genetic factors acting as regulatory elements of MTHFR methylation levels. In the present study we investigated several of the major polymorphisms in one-carbon metabolism genes as potential modulators of MTHFR gene methylation in blood DNA samples from 206 healthy individuals, observing a statistically significant contribution of the DNMT3B -149C>T one.…”

Section: Discussionmentioning

confidence: 99%

“…Particularly, increased MTHFR promoter methylation results in decreased gene expression levels and has been associated with male infertility, pre-eclampsia, recurrent miscarriages, trisomy 21 and congenital heart disease in the offspring [15,16,17,18,19,20,21]. MTHFR hyper-methylation is also suspected to play a role in diabetic complications, vascular diseases and cancer [22,23,24,25,26].…”

Section: Introductionmentioning

confidence: 99%

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Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Coppedè

Stoccoro

Tannorella

et al. 2019

IJMS

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Methylenetetrahydrofolate reductase (MTHFR) is a pivotal enzyme in the one-carbon metabolism, a metabolic pathway required for DNA synthesis and methylation reactions. MTHFR hypermethylation, resulting in reduced gene expression, can contribute to several human disorders, but little is still known about the factors that regulate MTHFR methylation levels. We performed the present study to investigate if common polymorphisms in one-carbon metabolism genes contribute to MTHFR methylation levels. MTHFR methylation was assessed in peripheral blood DNA samples from 206 healthy subjects with methylation-sensitive high-resolution melting (MS-HRM); genotyping was performed for MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), MTRR 66A>G (rs1801394), MTR 2756A>G (rs1805087), SLC19A1 (RFC1) 80G>A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp ins/del (rs34489327), DNMT3A -448A>G (rs1550117), and DNMT3B -149C>T (rs2424913) polymorphisms. We observed a statistically significant effect of the DNMT3B -149C>T polymorphism on mean MTHFR methylation levels, and particularly CT and TT carriers showed increased methylation levels than CC carriers. The present study revealed an association between a functional polymorphism of DNMT3B and MTHFR methylation levels that could be of relevance in those disorders, such as inborn defects, metabolic disorders and cancer, that have been linked to impaired DNA methylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Coppedè

Stoccoro

Tannorella

et al. 2019

IJMS

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“…Compared to subjects without complications, individuals with DN and hypermethylated profile in the MTHFR gene promoter showed higher levels of alpha-1 acid glycoprotein and total antioxidant capacity (50). In individuals carrying 677CC/1298AA haplotype, the hypermethylated profile was linked with higher fasting glycemia values (51).…”

Section: Sensitivity Analysis and Publication Biasmentioning

confidence: 98%

Association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms and the risk of diabetic nephropathy; a meta-analysis

Gupta

Sharma

Lakkakula³

et al. 2019

J Renal Inj Prev

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Methylenetetrahydrofolate reductase (MTHFR) is involved in the homocysteine metabolism. Two common variants of MTHFR gene (677C>T and 1298A>C), have been reported to reduce the MTHFR enzyme activity and leading to plasma hyperhomocysteinemia. There are a number of recent case-control studies that investigated the association between the MTHFR polymorphism and diabetic nephropathy (DN), albeit with inconsistent results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of MTHFR with susceptibility to DN. A literature search was conducted on PubMed, Embase and Google scholar from inception till March 18, 2019. For MTHFR 677C>T analysis, a total of 23 studies including DM controls (3095 cases and 3187 DM controls) and 12 studies including non-DM controls (1590 cases and 2052 nonDM controls) were taken. For MTHFR 1298A>C analysis, a total of 7 studies using DM controls (959 cases and 1209 DM controls) and 3 studies using non-DM controls (400 cases and 802 nonDM controls) were taken. Meta-analysis showed that mutant genotypes of the 677C>T (OR: 1.58; 95%CI: 1.16-2.14) and 1298A>C (OR: 1.38; 95%CI: 1.16-1.65) polymorphisms in the MTHFR gene were associated with increased risk of DN (diabetic kidney disease). MTHFR 677C>T and 1298A>C polymorphisms revealed significant heterogeneity between studies. Further, there was no evidence for publication bias for these polymorphisms. In conclusion, this meta-analysis provides strong evidence that MTHFR 677C>T and 1298A>C polymorphisms may be associated with increased risks of DN. However, further studies are still needed to accurately determine whether MTHFR genetic polymorphisms are associated with susceptibility to DN.

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“…This result was inverse for the MTHFR gene, that is, at LDL-C levels � 70 mg/dL, MTHFR methylation levels were higher. In the reviewed literature, hypermethylation of the MTHFR gene was associated with higher levels of TC and LDL-C in diabetic individuals [31]. MTHFR is an enzyme that acts on the folate cycle, and in MTHFR-deficient mice it was shown that the deficiency affects apolipoprotein levels and leads to lipid deposition [54].…”

Section: Plos Onementioning

confidence: 99%

“…The DNA methylation in specific genes involved in dyslipidaemia, i.e., in the increase or decrease in LDL-C values [12,30,31], the following are notable: the LPL gene, which encodes lipoprotein lipase (LpL), involved in the reduced conversion of very low-density lipoprotein (VLDL) into LDL-C in plasma [32]; the beta-adrenergic receptor 3 gene (ADRB3), which is involved in the regulation of lipolysis and thermogenesis in white and brown adipose tissue [33]; and the gene that encodes methylenetetrahydrofolate reductase (MTHFR), which is involved in the conversion of homocysteine (Hcy) into methionine [34] and may be involved in lipid metabolism, as observed in a study of MTHFR polymorphism and dyslipidemia [35].…”

Section: Introductionmentioning

confidence: 99%

The direct correlation between oxidative stress and LDL-C levels in adults is maintained by the Friedewald and Martin equations, but the methylation levels in the MTHFR and ADRB3 genes differ

et al. 2020

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Low-density lipoprotein (LDL-C) concentrations are a standard of care in the prevention of cardiovascular disease and are influenced by different factors. This study compared the LDL-C concentrations estimated by two different equations and determined their associations with inflammatory status, oxidative stress, anthropometric variables, food intake and DNA methylation levels in the LPL, ADRB3 and MTHFR genes. A cross-sectional population-based study was conducted with 236 adults (median age 37.5 years) of both sexes from the municipality of João Pessoa, Paraíba, Brazil. The LDL-C concentrations were estimated according to the Friedewald and Martin equations. LPL, ADRB3 and MTHFR gene methylation levels; malondialdehyde levels; total antioxidant capacity; ultra-sensitive C-reactive protein, alpha-1-acid glycoprotein, homocysteine, cobalamin, and folic acid levels; usual dietary intake; and epidemiological variables were also determined. For each unit increase in malondialdehyde concentration there was an increase in the LDL-C concentration from 6.25 to 10.29 mg/dL (p <0.000). Based on the Martin equation (≥70 mg/dL), there was a decrease in the DNA methylation levels in the ADRB3 gene and an increase in the DNA methylation levels in the MTHFR gene (p <0.05). There was a positive relation of homocysteine and cholesterol intake on LDL-C concentrations estimated according to the Friedewald equation and of waist circumference and age based on the two estimates. It is concluded the LDL-C concentrations estimated by the Friedewald and Martin equations were different, and the Friedewald equation values were significantly lower than those obtained by the Martin equation. MDA was the variable that was most positively associated with the estimated LDL-C levels in all multivariate models. Significant relationships were observed based on the two estimates and occurred for most variables. The methylation levels of the ADRB3 and MTHFR genes were different according to the Martin equation at low LDL-C concentrations (70 mg/dL).

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The MTHFR promoter hypermethylation pattern associated with the A1298C polymorphism influences lipid parameters and glycemic control in diabetic patients

Cited by 15 publications

References 25 publications

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

Association between the methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms and the risk of diabetic nephropathy; a meta-analysis

The direct correlation between oxidative stress and LDL-C levels in adults is maintained by the Friedewald and Martin equations, but the methylation levels in the MTHFR and ADRB3 genes differ

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