Genetics of homocysteine metabolism and associated disorders

Brustolin, Silvia; Giugliani, Roberto; Félix, Têmis Maria

doi:10.1590/s0100-879x2009007500021

Cited by 162 publications

(123 citation statements)

References 54 publications

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“…MTHFR is the key rate-limiting enzyme required for the conversion of dietary folate to 5-methyltetrahydrofolate, the methyl group donor required for the remethylation of Hcy to methionine in vivo (Kelly et al, 2002). One of its functional polymorphisms, A1298C, has been known to be associated with reduced enzymatic activity and increased plasma total homocysteine (tHcy) concentrations (Kumar et al, 2005;Brustolin et al, 2010;Klai et al, 2011). Homocysteine acts as a toxin with respect to endothelial cells, enhances vascular smooth muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis, thus directly inducing or acting in a synergistic manner with other factors in determining the appearance of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with stroke risk based on a meta-analysis

Lu²,

Wu³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Several independent studies have reported the role of the methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism in strokes, but the results are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed in the present study. In this meta-analysis, a total of 13 studies, including 1974 cases and 2660 controls, were selected to evaluate the possible association. Crude odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the strength of the association in additive, dominant, and recessive models. The overall analysis showed that MTHFR A1298C polymorphism and strokes MTHFR A1298C was associated with a significant increase in the risk of stroke in the heterozygote comparison (AC vs AA: OR = 1.17; 95%CI = 1.03-1.34) and in the dominant model (AC/CC vs AA: OR = 1.22; 95%CI = 1.01-1.49). Stratified analysis showed a significantly strong association between the MTHFR A1298C polymorphism and stroke risk in Asian populations (OR = 1.32 for AC vs AA; OR = 1.94 for CC vs AA; OR = 1.37 for AC/CC vs AA; OR = 1.33 for C vs A allele), but not in Caucasian populations. Additionally, the MTHFR 1298C allele was found to be a risk factor for developing ischemic strokes. However, no statistically significant increased risk of hemorrhagic stroke was found in any of the genetic models. In conclusion, this meta-analysis supported that the MTHFR A1298C polymorphism could be capable of increasing stroke susceptibility in Asian, but not in Caucasian, populations.

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Section: Discussionmentioning

confidence: 99%

Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with stroke risk based on a meta-analysis

Lu²,

Wu³

et al. 2013

Genet. Mol. Res.

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“…First, 5-methyltetrahydrofolate (5-methyl-THF) donates the N-5 methyl group to cobalamin, regenerating the unsubstituted tetrahydrofolate (THF) cofactor and methylcobalamin (10). Subsequently, cobalamin donates the methyl group to homocysteine, converting it to methionine (11).…”

Section: Introductionmentioning

confidence: 99%

Vitamin B-12 and Perinatal Health

Finkelstein

Layden

Stover

2015

Advances in Nutrition

122

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Vitamin B-12 deficiency (<148 pmol/L) is associated with adverse maternal and neonatal outcomes, including developmental anomalies, spontaneous abortions, preeclampsia, and low birth weight (<2500 g). The importance of adequate vitamin B-12 status periconceptionally and during pregnancy cannot be overemphasized, given its fundamental role in neural myelination, brain development, and growth. Infants born to vitamin B-12-deficient women may be at increased risk of neural tube closure defects, and maternal vitamin B-12 insufficiency (<200 pmol/L) can impair infant growth, psychomotor function, and brain development, which may be irreversible. However, the underlying causal mechanisms are unknown. This review was conducted to examine the evidence that links maternal vitamin B-12 status and perinatal outcomes. Despite the high prevalence of vitamin B-12 deficiency and associated risk of pregnancy complications, few prospective studies and, to our knowledge, only 1 randomized trial have examined the effects of vitamin B-12 supplementation during pregnancy. The role of vitamin B-12 in the etiology of adverse perinatal outcomes needs to be elucidated to inform public health interventions. Adv Nutr 2015;6:552-63.

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“…Hcy acts as a key intermediate in one-carbon metabolism being metabolized through two vitamin B-dependent pathways, which are controlled by three key enzymes-methylenetetrahydrofolate reductase (MTHFR), methionine synthase and cystathionine beta-synthase 1 A high blood concentration of Hcy has been recognized as an independent risk factor for cardiovascular diseases in observational studies, [2][3][4] and is also associated with several other disorders such as neural tube defects and non-syndromic oral clefts. 5,6 Although the benefits from homocysteine lowering interventions for cardiovascular diseases have not been confirmed, 7 it is plausible that the positive effect is exclusively related to stroke risk. 8 The inconsistency related to hyperhomocysteinemia as a cause of cardiovascular diseases could result from the interactions between nutrients, metabolic and genetic factors.…”

Section: Introductionmentioning

confidence: 99%

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort

et al. 2016

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BACKGROUND/OBJECTIVES: Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. SUBJECTS/METHODS: The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. RESULTS: Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers (⩾15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction o 0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction o 0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction o 0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. CONCLUSIONS: In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future.

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Genetics of homocysteine metabolism and associated disorders

Abstract: T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.]]>

Cited by 162 publications

References 54 publications

Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with stroke risk based on a meta-analysis

Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with stroke risk based on a meta-analysis

Vitamin B-12 and Perinatal Health

Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort

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