The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is not associated with Parkinson's disease.

Harmon, Dawn L.; Ramsbottom, Dorothy; Whitehead, Alexander S.; Ben‐Shlomo, Yoav; Davey-Smith, George

doi:10.1136/jnnp.62.6.671

Cited by 13 publications

(9 citation statements)

References 5 publications

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“…Other estimates of the frequency of the C677T MTHFR genotype in healthy Irish subjects, based on control groups in a study of Parkinson's disease 42 (nϭ184, C677T homozygote frequency 7.1%) and CAD 14 (nϭ61, C677T homozygote frequency 6.6%), indicate that the genotype frequency in Ireland is lower (Ϸ7.0%) than the 10.4% observed in the elderly control subjects reported above. When our control population is combined with these additional control groups, then the frequency of the homozygous C677T genotype is significantly higher in stroke cases (Pϭ0.01, odds ratioϭ2.0, 95% CIϭ1.2,3.4).…”

Section: Discussionmentioning

confidence: 89%

Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke

Harmon

Doyle

Meleady

et al. 1999

ATVB

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Abstract-Mild hyperhomocysteinemia is a risk factor for atherosclerotic vascular disease. Homozygosity for the C677T mutation in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) is frequently associated with hyperhomocysteinemia, particularly in individuals with low levels of serum folate, and has been directly associated with cardiovascular disease in certain populations. The purpose of this study was to establish whether the C677T mutation, which causes thermolabile MTHFR, is a risk factor for ischemic stroke in the Irish population. The homozygous C677T genotype has previously been associated with coronary heart disease in Ireland. We collected blood from 174 individuals (minimum age 60 years) who had suffered an ischemic stroke that was confirmed by computed tomography brain scan. Control subjects (nϭ183) aged Ն60 years, who had never suffered a stroke or transient ischemic attack, were recruited from hospitals and active retirement groups in the same geographical area. MTHFR genotypes were determined and other known risk factors for stroke were documented. In the control group, the frequency of subjects with the homozygous C677T genotype was 10.4%. In patients who had suffered ischemic stroke, the frequency was 15.5%. This difference was not statistically significant. 2 In addition it is associated with thickening of the carotid arterial wall. 3,4 The magnitude of the risk of vascular disease conferred by hyperhomocysteinemia varies between populations. A meta-analysis of the data indicates that hyperhomocysteinemia confers at least a 2.5-fold increased risk of stroke. 5 Homocysteine is a sulphur amino acid generated by the many transmethylation reactions that consume S-adenosyl methionine (SAM) (Figure). Homocysteine is remethylated to methionine (from which SAM is then regenerated) by the vitamin B12-dependent enzyme methionine synthase. This remethylation uses 5-methyl tetrahydrofolate as the methyl donor. 5-methyl tetrahydrofolate is itself generated from 5,10-methylene tetrahydrofolate by the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR). Under normal circumstances, homocysteine can be irreversibly degraded by the transsulfuration pathway, the first step of which is catalyzed by the vitamin B6-dependent enzyme cystathionine ␤-synthase (CBS).Plasma homocysteine levels are therefore influenced by both nutritional (folate and vitamins B12 and B6) and genetic factors, including mutations in the genes encoding methionine synthase, CBS, and MTHFR. In particular, a biochemically defined "thermolabile" variant of MTHFR is associated with moderate hyperhomocysteinemia. 6 The genetic change underlying thermolabile MTHFR is a C to T base transition at nucleotide 677 in the MTHFR cDNA, 7,8 which results in the substitution of valine for alanine. 8 The frequency of homozygotes for the thermolabile MTHFR mutation is between 5% and 15% in different European populations. 9 Recently, homozygosity for the thermolabile genotype has been associated with a nearly 10-fold increased risk of an indivi...

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Section: Discussionmentioning

confidence: 89%

Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke

Harmon

Doyle

Meleady

et al. 1999

ATVB

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“…Various mutations in genes involved in the homocysteine metabolism were reported, however, the C677T mutation in MTHFR gene showed significant association with homocysteine elevation. The frequency of C677T mutation varies between different population groups (Gallagher et al, 1996;Harmon et al, 1997). The frequency of this mutation in Indian population has not been established so far.…”

Section: Discussionmentioning

confidence: 98%

“…The frequency of this mutation in Indian population has not been established so far. Most of the studies reported an association between homozygous mutated genotype (TT) and elevated homocysteine (Harmon et al, 1997). However, there are few reports indicating the high prevalence of heterozygous genotype (CT) in certain populations and their association with hyperhomocystinemia (Sarinee et al, 2000;Ghosh et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study

Alluri¹,

Mohan²,

Komandur³

et al. 2004

Euro J of Neurology

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Elevated homocysteine level is an independent risk factor for ischemic stroke, thrombotic and cardiovascular diseases. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating the levels of homocysteine. A C677T mutation in this gene results in reduced activity. Sixty-nine patients with arterial stroke, six patients with venous stroke (confirmed by computed tomography and/or magnetic resonance imaging) with hyperhomocysteinemia were selected for the study. Forty-nine subjects with no past history of stroke served as controls. MTHFR genotypes were determined by PCR using specific primers, followed by restriction digestion and gel analysis. The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the patients with arterial stroke was 1.4% (one of 69) and 31.88% (21 of 69), respectively. There frequency was 16.6% (one of six) and 33.3% (two of six) in venous stroke. The genotyping results from controls showed that there was only one heterozygote out of the 49 studied (2.08%). There was a significant difference between the control and the patient groups. Odds ratio for the probability of the C677T MTHFR gene mutation in the patients versus control group was 22.29 (95% CI 4.89-98.8). This indicates that C677T MTHFR mutation is strongly associated with arterial stroke especially in young adults. MTHFR allele evaluation will help in preventing/reducing morbidity caused by stroke.

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“…The median duration of the disease was 6.6 years and ranged from three months to 40 years. The control population comprised two groups: one derived from a previous study24 was used to define the frequency of the MTHFR genotype frequencies in the Irish population (n=184). The second was a group of normal hospital personnel in whom a complete vitamin and homocysteine profile was obtained (n=89).…”

Section: Methodsmentioning

confidence: 99%

Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications

Mahmud

Molloy

McPartlin

et al. 1999

Gut

Self Cite

135

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Background-Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD. Aims-To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD. Methods-Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC). Results-Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn's disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B 12 levels were lower in patients with IBD irrespective of MTHFR genotype.Conclusions-There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B 12 therapy to protect against the thromboembolic complications of raised tHcy. (Gut 1999;45:389-394)

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The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is not associated with Parkinson's disease.

Cited by 13 publications

References 5 publications

Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke

Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke

MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study

Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications

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