Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke

Li, Zhaohui; Sun, Li; Zhang, Hongye; Liao, Yuhua; Wang, Daowen; Zhao, Bi; Zhu, Zhiming; Zhao, Jizong; Ma, Aiqun; Han, Yu; Wang, Yibo; Shi, Yi; Ye, Jue; Hui, Rutai

doi:10.1161/01.str.0000086753.00555.0d

Cited by 190 publications

(160 citation statements)

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“…Methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (ApoE), and angiotensin-converting enzyme (ACE) were chosen for further analysis, as, on review, those three genes were found to be studied well in Asian populations. Ten studies of MTHFR (Morita et al 1998;Zhang and Dai 2001;Wu et al 2001;Li et al , 2003Choi et al 2003;Baum et al 2004;Alluri et al 2005;Fang et al 2005;Gao et al 2006), six studies for ApoE (Kokubo et al 2000;Luthra et al 2002;Um et al 2003a;Jin et al 2004;Lin et al 2004;Gao et al 2006), and six studies of ACE (Doi et al 1997;Nakata et al 1997;Um et al 2001Um et al , 2003aGao et al 2006) gene polymorphisms were found to meet our selection criteria and were therefore included in the meta-analysis (Tables 2, 3 and 4). Because of unavailability of genotype data, two studies of ApoE polymorphism (Nakata et al 1997;Chowdhury et al 2001) were excluded for the present analyses.…”

Section: Data Synthesis and Statistical Analysismentioning

confidence: 99%

Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis

2006

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Stroke is a heterogeneous multifactorial disease and is thought to have a polygenic basis. Casecontrol studies on gene sequence variations have identified a number of potential genetic predisposition factors, but due to the conflicting results, uncertainty remains on the effect of these polymorphisms on risk for the development of stroke. To qualitatively and quantitatively assess the risk associated with different gene polymorphisms for stroke in Asian populations, we comprehensively searched and identified all the studies of association. Clinically overt case-control studies were selected only if neuroimaging had been used as the confirmatory measure for diagnosis of stroke. We performed a meta-analysis of the three most investigated genes, viz., methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (ApoE) and angiotensinconverting enzyme (ACE). Statistically significant association with stroke were identified for C677T polymorphism of MTHFR [random effects odds ratio (OR) = 1.47, 95% confidence interval (95% CI) 1.19, 1.82; P = 0.0004] and marginally significant association was detected with allele e 4 of ApoE (random effects OR = 1.47, 95% CI 1.00, 2.15; P = 0.049). The sensitivity analysis (exclusion of studies with controls not in HardyWeinberg equilibrium) revealed a significant association of stroke with the MTHFR C677T and ApoE e 4 alleles but showed no association with ACE gene insertion/ deletion polymorphism.

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Section: Data Synthesis and Statistical Analysismentioning

confidence: 99%

Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis

2006

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“…The majority of the unbound portion of Hcys is oxidized to form dimers (homocystine) or combined with cysteine to form mixed disulphides (Mansoor et al 1992;Ramakrishnan et al 2006). The excess of Hcys concentration is described in many human pathologies, including neurodegenerative diseases (Ravaglia et al 2005), thrombosis (Harpel et al 1996) and thrombosis-related diseases, like stroke (Boysen et al 2003;Li et al 2003).…”

Section: Introductionmentioning

confidence: 99%

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

Olas¹,

Kołodziejczyk²,

Malinowska³

2010

gpb

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Abstract. Homocysteine (Hcys) may be implicated in different diseases, especially in cardiovascular illnesses. The most reactive form of Hcys is its cyclic thioester -homocysteine thiolactone (HTL), which is formed in plasma and represents up to 0.29% of plasma total Hcys. Recently, it has been observed that Hcys and HTL may modify plasma proteins, including albumin, hemoglobin or fibrinogen, but the role of this process is not yet well known. The aim of our study in vitro was to investigate the modifications of human plasma total proteins after incubation with the reduced form of Hcys in concentrations 10-100 µmol/l, and HTL in concentrations 1-0.1 µmol/l, which correspond to levels found in human plasma during hyperhomocysteinemia in vivo. The aim of our study was also to explain the effects of Hcys and HTL on coagulation activity of human plasma. We showed that in model system in vitro Hcys and HTL change the level of thiol, amino and carbonyl groups in plasma total proteins. Moreover, our studies reported that not only Hcys (10-100 µmol/l), but also HTL (at lower concentrations than Hcys) modulates the coagulation properties of human plasma.

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“…Folate deficiency increases total homocysteine (tHcy) levels (4). Hyperhomocysteinemia is one of the risk factors of cardiovascular disease (4,5) and neural tube defects (NTDs) (6). Maintaining adequate blood folate levels and controlling tHcy levels are important in preventing these diseases.…”

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confidence: 99%

A Cross-Sectional Study to Find Out the Relationship of Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype with Plasma Levels of Folate and Total Homocysteine by Daily Folate Intake in Japanese

Fukuda

Hamajima

Wakai

et al. 2014

J Nutr Sci Vitaminol

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l-5-Methyl-tetrahydrofolate (THF), derived from dietary folate, is involved in the conversion of homocysteine into methionine ( Fig. 1; 1-3). Folate deficiency increases total homocysteine (tHcy) levels (4). Hyperhomocysteinemia is one of the risk factors of cardiovascular disease (4,5) and neural tube defects (NTDs) (6). Maintaining adequate blood folate levels and controlling tHcy levels are important in preventing these diseases.In the folate metabolic pathway, 5,10-methylene-THF is converted into 5-methyl-THF by the enzyme 10-methylene-THF reductase (MTHFR). In the MTHFR C677T polymorphism (rs 1801133), the T allele reduces thermostability of the enzyme and lowers its activity, which were found to be decreased by 30% in heterozygotes and by 65% in homozygotes of minor alleles compared with the CC genotype in an in vitro study (7). However, folate intake could increase blood folate levels even among those with the TT genotype. In previous observational studies, decreased tHcy levels were related to increased blood folate levels (8-11), and increased folate intake was associated with increased blood folate levels (8, 12) and decreased tHcy levels (8,13,14) in each of the MTHFR genotype. These correlations were substantially stronger among those with TT (8,9,[11][12][13][14][15] and those consuming relatively lower amounts of folate (8,12,13). In previous interventional studies using folate supplements or fortified foods, increased folate intake raised blood folate (16-21) and reduced tHcy levels (17-21).However, one study in Japan found no association of serum folate with energy-adjusted folate intake among those with the TT genotype (22). This may be partly explained by the difference in the amount of folate intake and sources of folate. The mean folate intake among Japanese aged 20 y or more was 329 mg/d for men and 189 mg/d for women and the mean intake from supplements or fortified foods among the population was only 1 mg/d in 2008 (23 (Received November 12, 2013) Summary In those with the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, enzyme activity is lowered. Therefore, these individuals might require an increased intake of folate to maintain or control blood levels of plasma folate or total homocysteine (tHcy). We examined associations of dietary folate intake with fasting plasma folate and total homocysteine (tHcy) according to genotype among 554 Japanese (207 men and 347 women aged 39-89 y) recruited in 2009. Intake of folate was estimated with a food frequency questionnaire. The MTHFR polymorphism was genotyped by a polymerase chain reaction with confronting two-pair primers. The log-transformed concentration of folate or tHcy was regressed on energy-adjusted folate intake in a linear regression analysis. Higher folate intake was associated with higher plasma folate among those with the CC (b50.165, p50.066) or CT (b50.248, p,0.001) genotypes, and with lower tHcy levels only among those with the CC (b520.141, p50.013) genotype. Plasma folate was significantly and inversely associat...

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Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke

Cited by 190 publications

References 45 publications

Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis

Association of gene polymorphism with genetic susceptibility to stroke in Asian populations: a meta-analysis

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

A Cross-Sectional Study to Find Out the Relationship of Methylenetetrahydrofolate Reductase (MTHFR) C677T Genotype with Plasma Levels of Folate and Total Homocysteine by Daily Folate Intake in Japanese

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