Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults

Kluijtmans, Leo A. J.; Young, Ian S.; Boreham, Colin; Murray, Liam; McMaster, Dorothy; McNulty, Helene; Strain, James J.; McPartlin, Joseph; Scott, John M.; Whitehead, Alexander S.

doi:10.1182/blood.v101.7.2483

Cited by 218 publications

(208 citation statements)

References 36 publications

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“…Furthermore, they showed that improved B 12 status was associated with this genotype. While this finding is contrary to those of previous studies [23], it does corroborate with our results. One explanation for the discrepancies between the conclusions of these studies is that the examined populations were different from one another in age.…”

Section: Discussionsupporting

confidence: 69%

“…Previous studies have shown that genetic polymorphisms may influence plasma concentrations of Hcy either directly or by affecting plasma folate concentrations [5,[20][21][22][23][24][25]. Here, the results indicate that the polymorphism MTHFR 677 TT is associated with a decrease in Hcy concentration.…”

Section: Discussionsupporting

confidence: 54%

“…Here, the results indicate that the polymorphism MTHFR 677 TT is associated with a decrease in Hcy concentration. This was an unexpected finding as previous studies have shown that the MTHFR 677 T allele is associated with reduced MTHFR enzyme activity [26] and increased Hcy concentration [5,20,[23][24][25]. Licastro et al [5] observed elevated Hcy concentrations in elderly DS individuals with the MTHFR 677 TT genotype; however, in other studies that used both children and adults with DS, no association between the MTHFR C677T polymorphism and Hcy concentration was seen [19,27].…”

Section: Discussionmentioning

confidence: 89%

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Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

et al. 2012

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Individuals with Down syndrome (DS) carry three copies of the Cystathionine b-synthase (CbS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 89%

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Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

et al. 2012

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“…To date, most studies have shown that the MTHFR C677T genotype is related to biomarkers, such as serum folate, tHcy concentration, and folate intake. Other polymorphisms in the folate pathway have been found to be associated with a variety of complex traits and disorders including MTHFR A1298C, MTRR A66G, MTR A2756G, MTHFD1 G1958A, FOLH1 T484C, SLC19A1 A80G, and transcobalamin II ( TCN2 ) C776G, the transport protein of vitamin B12 (Weisberg et al 1998; Gaughan et al 2001; Laverdiere et al 2002; Kluijtmans et al 2003; Dervieux et al 2004; Martinelli et al 2006; Moskau et al 2007; Silva et al 2011; Pangilinan et al 2012; Xie et al 2012). Table 1 summarizes the distribution of serum tHcy, folate, vitamin B6, and vitamin B12 according to polymorphisms related to folate and tHcy metabolism (Hiraoka et al 2004; Hiraoka et al 2009).…”

Section: Genetic Polymorphisms Related To Folate and Thcy Metabolism mentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

125

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Moderate hyperhomocysteinemia‐induced low folate status is an independent risk factor for cardiovascular disease, dementia, and depression. Folate is an essential cofactor in the one‐carbon metabolism pathway and is necessary in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. In the folate cycle and homocysteine metabolism, folate, vitamin B12, vitamin B6, and vitamin B2 are important cofactors. Many enzymes are involved in folate transport and uptake, the folate pathway, and homocysteine (Hcy) metabolism, and various polymorphisms have been documented in these enzymes. Serum folate and total Hcy (tHcy) levels are influenced by folate intake and genetic polymorphisms in 5,10‐methylenetertahydrofolate reductase (MTHFR) such as C677T. The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, with a frequency of approximately 15% in Japanese populations. Individuals with the TT genotype have significantly higher tHcy levels and lower folate levels in serum than those with the CT and TT genotypes. However, administration of folic acid has been shown to eliminate these differences. Moreover, data have suggested that interventions based on genotype may be effective for motivating individuals to change their lifestyle and improve their nutrition status. Accordingly, in this review, we discuss the effects of MTHFR C677T polymorphisms on serum tHcy and folate levels with folic acid intervention and evaluate approaches for overcoming folic acid deficiency and related symptoms.

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“…10 Several polymorphisms of genes involved in folate/homocysteine metabolism have been investigated for their effect on homocysteine level, but the most consistent and largest effect is observed for MTHFR C677T. [11][12][13] The association between a polymorphism and disease is not normally subject to the problems of confounding and reverse causation inherent in looking at associations between lifestyle factors and disease, 14 thus an association between MTHFR C677T and depression will add to the evidence implicating folate or its metabolites in this condition. Maternal folate intake during pregnancy is now an established risk factor for neural tube defects, and an association between the MTHFR C677T polymorphism and neural tube defects has been found comparing the mothers of cases and mothers of controls, but not when comparing the fathers.…”

Section: Introductionmentioning

confidence: 99%

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

et al. 2006

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Low dietary folate intake has been implicated as a risk factor for depression. However, observational epidemiological studies are plagued by problems of confounding, reverse causality and measurement error. A common polymorphism (C677T) in MTHFR is associated with methyltetrahydrofolate reductase (MTHFR) activity and circulating folate and homocysteine levels and offers insights into whether the association between low folate and depression is causal. We genotyped this polymorphism in 3478 women in the British Women's Heart and Health Study. In these women, we looked at the association between genotype and three indicators of depression; ever diagnosed as depressed, currently taking antidepressants and the EuroQol mood question. We also carried out a systematic review and meta-analysis of all published studies which have looked at the association between MTHFR C677T genotype and depression. In the British Women's Heart and Health Study, we found evidence of an increased risk of ever being diagnosed as depressed in MTHFR C677T TT individuals compared with CC individuals, odds ratio (OR) 1.35(95% CI: 1.01, 1.80). Furthermore, we identified eight other studies, which have examined the association between depression and MTHFR C677T. We were able to include all of these studies in our meta-analysis together with our results, obtaining an overall summary OR of 1.36 (95% CI: 1.11, 1.67, P = 0.003). Since this genotype influences the functioning of the folate metabolic pathway, these findings suggest that folate or its derivatives may be causally related to risk of depression.

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Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults

Cited by 218 publications

References 36 publications

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Genetic polymorphisms and folate status

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

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