Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homozygosity for a 677C-->T mutation at the locus that codes for 5,10-methylenetetrahydrofolate reductase (MTHFR), a folate-dependent crucial enzyme in homocysteine metabolism, may render the enzyme thermolabile and less active and has been associated with increased levels of plasma total homocysteine (tHcy). We assessed whether this mutation was associated with increased risk of coronary atherosclerosis and plasma levels of tHcy and furthermore studied whether folate status would modify the associations. Data were collected from subjects with substantial coronary atherosclerosis (> or = 90% occlusion in one and > or = 40% occlusion in a second coronary artery, referred to as cases, n = 131) or virtually no coronary narrowing (referred to as coronary controls, n = 87) and from a population-based control group (n = 100), all residing in the Rotterdam area, The Netherlands. Both males and females, aged 25-65 years were studied. The frequency of homozygosity for the mutation (+/+) in cases (10.0%) did not significantly differ statistically from that observed in coronary controls (11.5%, P = 0.71), population-based controls (7.0%, P = 0.43), or combined control groups (9.1%, P = 0.80). In the overall group (as well as in the three subgroups), plasma tHcy levels, fasting and to a lesser extent after a methionine-loading test, were higher in +/+ subjects than in homozygous normal subjects (-/-), whereas heterozygous subjects (+/-) had intermediate levels (Ptrend = 0.001). The +/+ subjects with erythrocyte folate levels < 790 nmol/l (population median) had a 77%, (95% CI, 27-144%) higher geometric mean fasting tHcy (21.4, micromol/l) than those with higher erythrocyte folate (12.1 micromol/l). The odds ratio (OR) of coronary atherosclerosis for +/+ subjects, with +/- and -/- subjects as the reference group, in analyses with combined control groups, was 1.1 (95% CI, 0.5-2.4). The ORs were 2.2 (95% CI, 0.7-6.8) and 0.6 (95% CI, 0.2-1.7) among subjects with low and high folate levels, respectively. Our study indicates that homozygosity for the 677C-->T MTHFR mutation, especially in combination with low folate status, predisposes to high plasma levels of fasting tHcy. However, homozygosity for this mutation, whether or not in combination with low folate status, was not associated with increased risk of coronary artery disease.
Atherosclerosis 1997 Jul 11
PMID:The 677C-->T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. 924 65

Hyperhomocysteinemia is an independent risk factor for atherosclerosis and cardiovascular disease. The cause of hyperhomocysteinemia is either an inborn metabolic defect or acquired. Main causes are either a defective homocysteine remethylation (thermolability of the enzyme 5,10-methylenetetrahydrofolate reductase) or nutritional deficiencies of B vitamins especially folic acid. The relative risk for myocardial infarction has been found of 3,1 in case of hyperhomocysteinemia. It is considered that a 5 microM/l homocysteine increment elevates vascular risk by as much as cholesterol increases of 20 mg/dl. B vitamins supplements are potentially useful.
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PMID:[Hyperhomocysteinemia: risk factor for premature atheromatosis]. 927 96

Homocysteine (Hcy) may represent a metabolic link in the pathogenesis of atherosclerotic vascular diseases and old-age dementias. Hyperhomocysteinemia is an independent risk factor for coronary artery disease and peripheral vascular disease, and is also associated with cerebrovascular disease; specifically, the risk of extracranial carotid atherosclerosis significantly increases in relation to Hcy levels. Hcy is a reliable marker of vitamin B12 deficiency, a common condition in the elderly which is known to induce neurological deficits including cognitive impairment; a high prevalence of folate deficiency has been reported in psychogeriatric patients suffering from depression and dementia. Both these vitamins occupy a key position in the remethylation and synthesis of S-adenosylmethionine (SAMe), a major methyl donor in CNS; therefore, deficiencies in either of these vitamins lead to a decrease in SAMe and increase in Hcy, which can be critical in the aging brain. Another pathogenetic mechanism linking high Hcy levels to reduced cognitive performances in the elderly might be represented by excitotoxicity, since hyperhomocysteinemia may lead to an excessive production of homocysteic acid and cysteine sulphinic acid, which act as endogenous agonists of NMDA receptors. Considering the reasonably high prevalence in the general population of a genetic predisposition to a thermolabile form of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), hyperhomocysteinemia can be seen as the result of multiple genetic and environmental factors leading to vascular and/or neurodegenerative disorders where age-related involutive phenomena represent a common pathogenetic ground. Systematic studies in different psychogeriatric conditions monitoring Hcy levels and clinical features before and after vitamin supplementation are therefore highly recommended.
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PMID:Role of homocysteine in age-related vascular and non-vascular diseases. 935 35

A common mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene results in elevated homocysteine levels and, presumably, in increased atherosclerotic risk. We evaluated serum homocysteine levels, MTHFR genotype, and a panel of variables in a sample of 155 middle-aged Italian subjects (mean age 38.1 years). Biometrical, hematological, and biochemical variables (including serum folate and vitamin B12) and lifestyle characteristics were investigated. MTHFR genotype was studied by polymerase chain reaction. The frequency of the genotype Val/Val (homozygosity for the mutant allele) was 16.13%. The Val/Val genotype was associated with increased levels of homocysteine; no differences among genotypes were seen in individuals with folate or vitamin B12 levels at or above the median values. In multivariate analysis, MTHFR genotype was an independent predictor of homocysteine levels in both biochemical and non biochemical regression models. Sex and diastolic blood pressure emerged as non biochemical variables independently associated with homocysteine. Apart from cofactors, uric acid was the only biochemical variable independently associated with homocysteine, particularly in subjects with Val/Val genotype. The observed parallel increases in homocysteine and uric acid levels in subjects with thermolabile MTHFR warrant further investigation.
Atherosclerosis 1998 Aug
PMID:Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine and other risk factors for vascular disease. 971 45

To explore the hypothesis that an interplay between genetic and environmental factors contributes to the development of coronary atherosclerosis, we compared the prevalence of risk factors for atherosclerosis among survivors of myocardial infarction (MI) and their spouses and apparently healthy men and women (spousal pairs) with no personal and family history of atherosclerosis in three generations. There were no significant differences in life-style and dietary habits between the groups. The daily vegetable and/or fruit intake was generally low and did not differ between the groups. Thirty percent and 25% of men and women did not consume any vegetables or fruits, respectively. All differences found in the male MI survivors and control men were also found between the female groups: MI survivors and their spouses were significantly more obese and had higher systolic and diastolic blood pressure and more pathologic plasma lipid levels compared with control males and females, respectively. Compared with the control men and women, MI survivors and spouses had higher plasma homocysteine (Hcgamma) levels (15.3 +/- 10.5, 11.9 +/- 4.0, 16.9 +/- 5.5, and 14.3 +/- 4.0, micromol/L, respectively, P = .01). The frequency of the homozygous C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism in MI survivors was twice that observed in their spouses and controls (12.1%, 4.8%, and 5.8%, respectively), but this difference did not reach statistical significance. A statistically significant association of the MTHFR genotype and Hcgamma concentration (multiple ANOVA) was shown. Neither the frequencies of apolipoprotein E (apoE) alleles nor Asp9Asn mutation of exon 2, Asn29lSer mutation of exon 6, and Ser447Ter of exon 9 of the lipoprotein lipase (LPL) gene varied significantly among the groups. A possible explanation for our findings is that individuals with a genetic predisposition for atherosclerosis and their spouses share a life-style that results in a higher body mass index (BMI) and waist to hip ratio (WHR). On the other hand, individuals with no family history of atherosclerosis, despite an unhealthy life-style similar to that in the affected families (diet and physical activity), had a lower BMI and WHR and more favorable metabolic parameters, including plasma Hcgamma. In conclusion, we have shown that a personal and/or family history of atherosclerosis corresponds to the prevalence and level of risk factors for atherosclerosis. A combination of life-style factors and inherited metabolic abnormalities, including high plasma Hcgamma, are the more likely explanation for our findings.
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PMID:Risk factors for atherosclerosis in survivors of myocardial infarction and their spouses: comparison to controls without personal and family history of atherosclerosis. 1117 70

The aim of the study was to determine whether folic acid treatment in subjects with homocysteinemia would change their coagulation and oxidative status. Thirty-three patients with peripheral vascular disease and 26 elderly subjects with no symptoms of atherosclerosis, all of whom had total homocysteine >20 microM, were treated with folic acid (5 or 10 mg) for 3 months. In the 33 patients with peripheral vascular disease, homocysteine levels decreased from a median of 26.7 microM at baseline to 20.0 microM (p < 0.0001), whereas in the 26 asymptomatic elderly subjects, homocysteine level decreased from 24.4 microM to 18.6 microM (p < 0.0001). Plasma fibrinogen decreased whereas plasminogen and anti-thrombin increased; the differences between pre- and posttreatment values were significant in both patients and healthy subjects. Oxidative status markers showed a shift toward lower oxidative stress. This effect was observed in both study groups. An association of the therapeutic effect with the genetic polymorphism of 5,10-methylenetetrahydrofolate reductase was not detected. Folic acid supplementation to hyperhomocysteinemic subjects resulted in a decrease in total blood homocysteine concentrations; moreover, there was a tendency to reverse the coagulation status and oxidative stress.
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PMID:Treatment of hyperhomocysteinemia with folic acid: effects on homocysteine levels, coagulation status, and oxidative stress markers. 1202 79

High plasma homocysteine, a risk factor for atherosclerosis, is frequently caused by a common mutation in the gene for the enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR), C677T (alanine to valine substitution) or low intake of B vitamins that affect the remethylation or transsulfuration pathways in homocysteine metabolism. However, the interaction of the C677T mutation and B vitamins other than folate has not been well elucidated. We conducted a cross-sectional survey of 324 men and 641 women who participated in a 1996 health examination under a hypothesis that high nutritional status of folate, vitamin B12 and vitamin B6 expressed as high serum levels, may compensate for the hyperhomocysteinemia associated with homozygosity for the C677T mutation, but not for having the mutation per se. Age-adjusted plasma homocysteine levels were higher for both men and women with the homozygous genotype for the mutation than those who were heterozygous or had no mutation. Elevated homocysteine levels in homozygous genotype was attenuated among persons with higher serum levels of vitamin B12 and folate, but not vitamin B6, and among persons with the combination of lower folate and higher vitamin B12 and of higher folate and higher vitamin B12, split by the median. These findings suggest that elevated homocysteine levels among Japanese with the homozygous genotype for the MTHFR gene mutation can be modified efficiently by dietary supplement of vitamin B12 as well as folate.
Atherosclerosis 2002 Oct
PMID:Effects of serum B vitamins on elevated plasma homocysteine levels associated with the mutation of methylenetetrahydrofolate reductase gene in Japanese. 1220 4

In recent years, an intense interest has developed in the association between Parkinson's disease (PD) and hyperhomocysteinemia. Homocysteine (Hcy) is a neuronal excitotoxic amino acid, and is well known as a risk factor for vascular diseases. Some reports suggest that the administration of L-DOPA may promote hyperhomocysteinemia and idiopathic atherosclerosis. In this study, we report that a mild hypertrophy of the intima-media complex (IMC) of the carotid artery, which has been established as a marker for systemic atherosclerosis, is observed in PD patients compared with normal subjects. PD patients that were treated with L-DOPA for long durations showed a hypertrophic IMC, while the patients that were not treated with L-DOPA did not show any hypertrophic changes in the IMC. These hypertrophic changes were observed primarily in patients with a Hoehn-Yahr stage of 3-5. PD patients with hypertrophic IMC of the carotid artery also exhibited elevated plasma levels of Hcy associated with the C677T genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR). Moreover, a prolonged duration of treatment with L-DOPA in patients with MTHFR T/T genotype enhanced the hypertrophy of IMC, compared with patients with the C/C or C/T genotype. These results suggest that hyperhomocysteinemia promoted by the C677T genotype of MTHFR and prolonged treatment with L-DOPA enhances atherosclerosis in PD patients and affects their general condition.
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PMID:Hypertrophy of IMC of carotid artery in Parkinson's disease is associated with L-DOPA, homocysteine, and MTHFR genotype. 1261 26

The lesions of coronary atherosclerosis represent the result of a complex, multicellular, inflammatory-healing response in the coronary arterial wall. In vivo and in vitro cellular and molecular studies have suggested a role for tissue homocysteine in endothelial cell injury and adverse extra-cellular matrix remodeling. Gene polymorphisms in relation with numerous risk factors might increase the incidence of coronary artery disease (CAD). In this review we have focused on the correlations between plasma homocysteine levels, the incidence of cardiovascular disease and the cytosine-to-thymidine substitution at nucleotide 677 (C677T) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, coding for a key enzyme in methionine-homocysteine metabolism. The role of the C677T MTHFR gene polymorphism in the causation of CAD is controversial. We reviewed 12 recent case-control studies comprising 5370 genotyped patients with CAD and 4961 genotyped participants without CAD. There was no significant difference between those with and without CAD in the frequency of the C677T polymorphism (34.9 vs 33.6%). The frequency of homozygous C677T polymorphism in these groups was 10.9 versus 12.8%, respectively, although there were some ethnic differences in the C677T MTHFR polymorphism. In the analysis of the 12 studies, the odds ratio of CAD associated with the TT genotype (homozygous C677T polymorphism) was 1.18. Only slightly higher plasma homocysteine levels were observed in participants with the val/val (TT) genotype (14.4+/-2.9 micro mol/L in TT genotype vs 11.1+/-1.9 and 11.9+/-2 micro mol/L in CC and CT genotype, respectively). In addition, the relation between homocysteine increase after methionine loading and MTHFR genotypes is also controversial. However, hyperhomocysteinemia because of the C677T MTHFR allele may be corrected with oral folic acid therapy. Further investigations on the relationships between MTHFR genotypes and the incidence of CAD should be based on larger samples, paying attention to the differences between various ethnic populations. Individual therapeutic strategies based on single nucleotide polymorphism may become increasingly important for preventive treatment against polygenic CAD.
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PMID:Correlation between C677T MTHFR gene polymorphism, plasma homocysteine levels and the incidence of CAD. 1472 17

Elevated homocysteine is a risk marker for several human pathologies. Risk factors for elevated homocysteine include low folate and homozygosity for the T allele of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Because nitric oxide may inhibit folate catabolism and endothelial nitric oxide synthase activity is reduced in smokers, we postulated that smoking status might modify the impact of the MTHFR C677T polymorphism on homocysteine (tHcy) concentrations. We tested this hypothesis in a healthy young adult population for which MTHFR C677T genotypes and tHcy concentrations were previously reported. The MTHFR 677TT genotype was significantly associated with elevated tHcy concentrations in smokers (P = 0.001) but not in non-smokers (P = 0.36). Among smokers, the MTHFR 677TT genotype was significantly associated with high tHcy in heavy smokers (P = 0.003) but not light smokers (P = 0.09), in men (P = 0.003) but not women (P = 0.11), and in subjects from the lowest serum folate quartile (P = 0.49) but not from folate quartiles 2-4 (P = 0.49). After adjustment for nutritional variables, interactions between MTHFR C677T genotype and NOS3 G894T genotype, and between MTHFR genotype, smoking status and gender were statistically significant. We propose that hyperhomocysteinemia in MTHFR 677TT homozygote smokers is the consequence of mild intracellular folate deficiency caused by a smoking-related reduction of NOS3 activity that is exacerbated when serum folate is low.
Atherosclerosis 2004 Jun
PMID:The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. 1513 61


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