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Hyperhomocysteinemia as a result of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism causes an increased risk of cerebrovascular disease: a biochemical perspective.

Introduction

There is much investigation today into the relationship of elevated homocysteine and cardiovascular disease. Homocysteinemia is widely associated with cardiovascular disease in the form of atherosclerois, myocardial infarction, peripheral arterial disease, venous thrombosis, hypertension, and cerebrovascular disease. Considerable speculation exists to the adverse effects of elevated homocysteine and neural tube defects, colorectal cancer, and dementia. This research paper is an attempt to explore homocysteinemia as a causative agent in cerebrovascular disease and stroke.

Homocysteine has the molecular formula HSCH2CH2CH(NH2)CO2H. Homocysteine cannot be obtained through the diet. It is made from the amino acid methionine by the removal of its terminal methyl group. Homocysteine can be regenerated into methionine or converted into cysteine through the utilization of folic acid and vitamin B12. Homocysteine is similar to the amino acid cysteine but differs in that it has one additional methylene group.

Elevated homocysteine in the blood is termed homocysteinemia and in the urine, homocysteinuria. Homocysteine is currently utilized as a laboratory marker of cardiovascular heart disease such as stroke, atherosclerosis, CVD, and hypertension. This cardiovascular disease risk has been documented to be readily remedied with folic acid therapy. Homocysteine is methylated to methionine by the transfer of the methyl group of methytetrahydorfolate (MTHF). Methylenetetrahydrofolate is made by the reduction of a methylene group of methylenetetrahydrofolate. The reduction of methylene of methylenetetrahydrofolate is catalyzed by methylenetetrahydrofolate reductase enzyme. (1) In this remethylation process of homocysteine, 5MTHF and methylcobalamin form a prosthetic group for the enzyme methionine synthase. Methylcobalamin is the methyl donor necessary to make homocysteine into methionine. Conversely, methionine is converted to homocystiene in the following mechanism. Methionine is converted to S-adenosylmethione (SAM) catalyzed by methionine adenosyl transferase. The methyl group is taken from SAM to form S-adenosyl homocysteine (SAH). When the adenosyl group is taken from SAH, homocysteine is formed. MTHFR enzyme normally converts dietary folate into its active cofactor in homcystcinc metabolism. MTHFR converts 5, 10-methylene THF to 5-methyl THF. MTHFR needs FAD of riboflavin as a prosthetic group. A genetic mutation in the MTHFR enzyme is ultimately what is implicated in cardicovascular disease and, specifically, stroke.

The mutation (677C-T) in the methylenenetetrahydrofolate reductase enzyme gene results in reduced folate dependent enzyme activity and reduced remethylation of homocysteine to methionine. (2) The number of C677T/MTHFR mutant homzygotes are classified TT genotype, mutant heterozygous CT genotype and normal homozygous CC genotype of wild type. (3) The mutation in the MTHFR gene is a C--T substitution at the base pair 677 which causes an exchange of an alanine to a valine. (4) It has been determined that the mutation is present in 35% of alleles and that the TT genotype mutant homozygotes have elevated average plasma homocysteine concentrations compared to those not carrying the mutant allele (CC genotype.) This thermolabile MTHFR causes the decreased enzyme activity that elevates plasma homocysteine levels. As a result, this common C677T/MTHFR mutation is considered to be a frequent genetic risk factor for cardiovascular disease and stroke. (5) There is speculation that MTHFR deficiency may be caused by other types of gene mutations but the current evidence is lacking.

A substantial number of studies have been conducted to investigate the relationship between the C677T/ MTHFR genetic mutation and stroke etiology, however the biochemical mechanism to explain such has been elusive.

Methods

A computerized search of The U.S. National Library of Medicine and the National Institute of Health PubMed was conducted. The search was conducted through the journals database, MeSH database, clinical queries, and single citations. The journal database was filtered to include journals of biochemistry, genetics, cardiovascular disease, and nutrition only. The MeSH search utilized the terms homocysteine, MTHF, MTHFR, amineoxoreductases, cardiovascular disease, stroke, and polymorphism. Included in the clinical queries and single citations were three meta-analyses, four prospective studies, three retrospective studies, four observational studies, two case reports, two editorials, and one animal model with a MTHFR deficiency. A total of 17 refereed peer-reviewed published articles were critically analyzed and comprise the basis of this research paper. This research paper will attempt to present evidence demonstrating the relationship between the MTHFR polymorphism and stroke and to address the biochemical and mechanical significance of the MTHFR polymorphism, hyperhomocysteinemia and stroke.

Data

MTHFR gene polymorphism was studied in 58 ischemic stroke patients in a tertiary care hospital setting in India. (6) In their introduction, the authors acknowledge that more than 110 inheritable, 175 genetic loci and 2050 different mutations that predispose one to stroke have been identified. (7) Ischemic stroke can result from one genetic defect or a combination of defects such as apoprotein E 4 and angiotensin coverting enzyme D/D genotypes. Other factors such as smoking, hypertension, and ethanol use in combination with these genetic mutations can provoke stroke. The authors state that the role of elevated homocysteine (Hey) is a relatively new established risk factor for cardiovascular disease. (8) Homocysteine role in stroke is controversial although most case control studies indicate a causal relationship. (9)

Three months following stroke fasting blood was drawn and evaluated for folic acid, vitamin B12, and homocysteine. MTHFR gene analysis was conducted by extracting DNA from peripheral leukocytes. The MTHFR C-T677 substitution was identified by using enzyme digestion restriction of the polymerase chain reaction (PCR) products. (10) In the study 32.8% of patients had MTHFR C677T gene polymorphism, 3 were homozygous (TT), 16 heterozygous (TC), and the balance of patients were normal (CC). (11) Homocysteine levels were highest in TT alleles compared to TC and CC. The authors contend that the need of 5-methyltetrahydrofolate as a methyl group donor for conversion of methionine to homcystiene might account for the slight rise of serum homocysteine in homozygous patients. (12) It is known that the influence of MTHFR genotype on HCy is greater in individuals with low serum folate and B12 levels. (13) The authors suggest that that a diet high in B12 and folate could supercede a folate deficiency even in a MTHFR polymorphic patient. The authors concluded that MTHFR gene polymorphism was noted in 1/3 of patient with ischemic stroke and that the rise in homocysteine was not significantly greater than those patients without the polymorphism.

A similarly designed study published in the European Journal of Neurology in 2005 indicated a C677T MTHFR mutation was strongly associated with arterial stroke especially in young adults. (14) Sixty-nine patients with arterial stroke were studied and 49 patients with no previous history of stroke were the control group. MTHFR genotyping was conducted by PCR with specific primers and with subsequent restriction digestion and gel analysis. The authors detected 1.4% (one of 69) homozygous and 31.88% (21 of 69) heterogygous MTHFR mutant genotype. (15) The control group had only one heterozygote out of 49 (2.08%) tested. The odds ratio for the probability of the C677T MTHFR gene mutation in stroke patients compared to control group was 22.29 (95% CI 4.89-98.8). (16) The authors recommended allele evaluations in the future to reduce and prevent stroke morbidity.

A Japanese study published in 1998 showed a risk of stroke 2.05 times greater with individuals with the TT genotype and 1.35 times greater with the TC genotype than controls. (17) Their study indicated the prevalence of stroke in patients with the mutated gene to be almost two-fold relative to recent European studies.

Rates of the 677T polymorphism vary greatly among Asian, black, and white ethnic groups. These groups may, however, show different carrier rates or environmental susceptibility to polymorphisms which could account for geographical and ethnic variances in stroke risk. (18)

In a meta-analysis published in Stroke in 2005 the authors evaluated 13 papers of which only 5 categorized specific TT genotype frequencies. No association was found between TT genotype and large artery, small artery, and cardioembolic stroke. (19) In the Stroke metaanalysis of 15,000 individuals, the MTHFR 677C-T polymorphism showed an elevated risk of stroke that was gradient in nature and dose-dependent. Their estimate of TT homozygotes was two times that seen in heterozygotes inferring an additive influence of the T allele on stroke risk. (20) Their finding may have significant public health considerations as 3-50% of most populations are CT heterozygotes and 3-15% are TT homozygotes. (21) The authors in the Stroke meta-analysis conclude that, " there is evidence in support of a causal role for homocysteine in the etiology of ischemic stroke due to atherosclerosis and other mechanisms, as it is implausible that the 677C-T variant exerts its influence other than by impaired metabolism." (22) The authors also support folic acid fortification programs as providing benefit in preventing stroke by inhibiting the influence of the MTHFR 677C-T substitution on plasma homocysteine by facilitating homocysteine remethylation to methionine. (23)

A 2006 hospital based study of 32 acute ischemic stroke patients demonstrated four of 32 patients (12.5%) had high homocyteine levels. (24) Three of these four subjects were homozygous TT for MTHFR polymorphism and of these three, two had low serum folate. Five of all the total 32 subjects (18.8%) were heterozygous (CT) genotype. The researchers stated the hyperhomocysteinemia due to MTHFR C677T homozygous genotype is a risk factor for ischemic stroke and the folate levels may modify the presentation of the MTHFR TT genotype. (25)

Lars Brattstrom, DE, et. al., published a large meta-analysis in Circulation in which they concluded methylenetetrahydroflate reductase gene mutations cause hyperhomocysteinemia but do necessarily lead to vascular disease. (26) Although they noted those individuals that possessed TT genotype had an average of 25% higher mean total plasma homocysteine concentrations than the normal CC genotype, they noted no overall increase risk of cardiovascular disease (CVD.) (27) The authors elucidate other factors such as blood pressure, elevated total cholesterol, and lack of exercise as causative agents in hyperhomocysteinemia. Because renal function is a major marker of plasma homocysteine concentration, the authors consider aberrant renal function due to hypertension and atherosclerosis as major factors in elevated homocysteine compared with MTHFR genotype mutations. (28)

Discussion

The preponderance of evidence suggests the MTFIFR mutation in the homozygous form and in the presence of folate deficiency leading to hyperhomocysteinemia is a provocative agent in cerebrovascular disease.

One meta-analysis showed that patients with the C677T TT genotype had a higher odds ratio of CVD disease compared to the CC genotype when the patients had low folate status. This demonstrated that high nutritional folate intake modifies the effect of the MTHFR T allele which in turn causes a smaller increase in homeysteine levels which could positively effect the risk of stroke associated with the polymorphism. This would propose a link of the effect of the MTHFR polymorphism on cerebovascular disease risk.

My research also displays conflicting evidence in the association between the MTHFR deficiency and some forms of cardiovascular disease. Two case studies support the association of MTHFR defect and stroke, however, two prospectives, one meta analysis, and two observational studies were contradictory. One of the observational studies suggested that plasma homocysteine increases were the result of increased homocysteine secretion and renal disease rather than cerebrovascular disease. This suggestion was supported by observations that the C677TTT genotypes had higher homocysteine levels but not comparable risk of cerebrovascular disease.

The biochemical and mechanistic etiology that is responsible for stroke provocation is more obscure in the medical literature. A number of mechanisms have been purported to demonstrate why hyperhomocysteinemia can promote atherogenesis and cerebrovascular insult. Speculation on the mechanisms by which hyperhomocysteinemia promotes cerebrovascular disease include the genesis of platelet adhesiveness and clotting, and initiating growth of smooth muscle cells. This proliferation of smooth muscle cells may cause vascular lesions in the endothelium (29) Excess homocysteine can form homocysteine thiolactone (HCTL) which thiolates free amino groups in low density lipoproteins and causes them to be enveloped by macrophages which then form foams cells and atherosclerotic plaques in the endothelium. (30) Homocysteine is transformed into this cyclic thioester (HCTL) instead of being transferred into tRNA and made into proteins. (31)

Homocysteine is activated by the enzyme methionyl-tRNA synthetase. In a process termed N-homo-cysteinylation, atherogenesis may be caused in individuals with hyperhorncysteinemia. In this mechanism, homocysteine thiolactone acylates free amino groups of protein lysine remnants. (32) This changes the biochemical properties of proteins, specifically, lipoproteins and their role in atherosclerosis. Homocysteinylation of low-density lipoproteins (LDLs) favors oxidation and destruction by macrophages. (33)

Homocysteinylated LDL also cause a humoral immune response as anti-homocysteinyllsine antibodies have been detected in plasma of patients with cerebral stroke. (34) Homocysteine thiolactone is hydrolyzed to homocysteine by paraoxonase, a calcium-dependent esterase synthesized in the liver and contained in plasma high-density lipoproteins (HDLs). (35)

In a paper published in Amino Acids in 2007 the authors propose mechanisms of human toxicity by hyperhomocysteinemia. (36) The authors state that, by the incorporating of homocysteine into lipoproteins via disulfide or amide linkages (S-homocysteiny!ation or N-homocysteinylation), lipoprotein structure and function is altered. (37) The authors conclude that protein N-homocysteinylation causes cellular toxicity and promotes an autoimmune response which causes athero-genesis. (38) Due to the fact that homocysteine is proinflammatory, pro-thrombotic, and causes endoplasmic reticulum oxidative changes, the homocysteinylation mechanism is a very plausible explanation for inducement of cerebrovascular incidents.

Homocystiene also causes lipid peroxidation and free radical formation. A significant number of patients with atherosclerosis and stroke have been found to be deficient is cystathione synthase activity. (39) Cystathionine beta synthase is necessary to catalyze the condensation of homocysteine and serine to cystathionine in the transsulfuration pathway. Elevated levels of homcys-teine and methionine caused by the cystathonine beta synthase deficiency are features of homocystinuria, an accumulation of homocysteine in the urine. (40) Homocystinuria is rare autosomal recessive disorder in which many patients have thrombolytic events before 30 years of age. It has been established that reducing elevated homocysteine levels due to cystathione beta-synthasc deficiency of homocystinuria absolutely reduces cardiovascular risk. (41) Although the accumulation of homocysteine is not via the MTHFR mutation, this mechanism can explain platelet aggregation and thrombosis associated with hyperhomocysteinemia seen in stroke.

Another possible mechanism considers the fact that the production of homocysteine pathways circumvent production of glutathione and methionine, which are necessary to impede atherosclerosis and thrombotic lesions. Researchers in the Department of Clinical Chemistry University Hospital in Lund Sweden investigated the different fractions of homocysteine and their relation to different fractions of glutathione and cysteine in stroke patients and control subjects. (42) They noted that extracellular glutathione and cysteine influenced the formation of different homocysteine species. In patients with high concentrations of total plasma homocysteine they noted a lower ratio of reduced to total plasma homocysteine compared to a group of patients with lower concentration of total plasma homocysteine. (43) The low reduced to total ratio of plasma homocysteine in combination with elevated plasma homocysteine concentrations, they postulated, could demonstrate an increased pro-oxidant activity in plasma in these stroke patients. Therefore, accelerated pro-oxidant mechanisms in plasma could be a factor that could explain hyperhomocysteinemia. (44) The atherosclerotic and thrombotic nature of stroke may be explained by the increased anti-oxidant capabilities of hyperhomocysteinemia.

Another mechanism considers premature degradation of arterial elastic fibers by hyperhomocysteinemia induced elastolytic action. This was noted in hyperhomocysteinemia associated with aortic dissection. (45) Homocysteinylation via homocysteine thiolactone of elastic proteins in arterial walls termed fibrillin-1 caused reduction of arterial elasticity. (46) Fibrillin-1 is the primary ingredient of microfibrils that form a sheath surrounding the amorphous elastin in endothelial tissue. These microfibrils are composed of end-to-end polymers of fibrillin. Researchers noted that reduction defects in fibrillin-1 caused formation of elastin that was abnormally aggregated and more easily degraded by matrix metalloproteinases than normal elastin. (47) The researchers subsequently observed upregulation of synthesis of matrix metalloproteinases, progressive destruction of connective tissue by the enzymes and the development of aneurysms. (48) MTHFR defects that cause homocysteine elevations associated with stroke could presumably trigger endothelial damage via this mechanism.

Evidence suggests that homocysteine may function as a physiological mediator of the endothelial matrix. (49) Other oxidative mechanisms and the resultant decreased biological activity of endothelium-derived nitric oxide (NO) may also contribute to homocysteine associated endothelial damage. (50) Nitrous oxide deprivation is present in the pathomeehanics of stroke. It is interesting to note that many cardiac patients receive NO pre-operatively as anesthesia. This nitrous oxide impairs methionine synthase inhibiting folate synthesis and causing postoperative hyperhomocysteinemia. Nitrous oxide anesthesia has been shown to promote postoperative endothelial dysfunction.

The study of nutrigenomics may be the solution to the link between MTHFR deficiency and cerebrovascular disease. Nutrigenomics considers how nutrients modulate gene and protein expression and influence cellular metabolism. (51) Nutrigenomics is essentially the combination of molecular nutrition and genomics. (52) It is worth exploring how folic acid and vitamin B12 could potentially complete polymorphic gaps in our DNA, could work with DNA to synthesize the appropriate proteins, and, presumably, interfere with the expression of genes that cause cardiovascular disease and stroke. (53)

Conclusion

The results of this investigation support the hypothesis that impaired folate metabolism via the MTHFR genetic mutation, resulting in high homocysteine levels, is causally related to increased risk of cerebrovascular disease and stroke.

References

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by: Robert A. Duca, Jr. DC, MS, DABCI, DACBN, DABCSP
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