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1.
Homocysteine - from disease biomarker to disease prevention.
Smith, AD, Refsum, H
Journal of internal medicine. 2021;(4):826-854
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Abstract
We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age-related conditions are also associated. Few other disease biomarkers have so many associations. The clinical importance of these associations becomes especially relevant if lowering plasma total homocysteine by B vitamin treatment can prevent disease and so improve health. Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly. We conclude from our review that total homocysteine values in adults of 10 μmol/L or below are probably safe, but that values of 11 μmol/L or above may justify intervention. Homocysteine is more than a disease biomarker: it is a guide for the prevention of disease.
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Homocysteine: Its Possible Emerging Role in At-Risk Population Groups.
Azzini, E, Ruggeri, S, Polito, A
International journal of molecular sciences. 2020;(4)
Abstract
Increased plasma homocysteine is a risk factor for several pathological disorders. The present review focused on the role of homocysteine (Hcy) in different population groups, especially in risk conditions (pregnancy, infancy, old age), and on its relevance as a marker or etiological factor of the diseases in these age groups, focusing on the nutritional treatment of elevated Hcy levels. In pregnancy, Hcy levels were investigated in relation to the increased risk of adverse pregnancy outcomes such as small size for gestational age at birth, preeclampsia, recurrent abortions, low birth weight, or intrauterine growth restriction. In pediatric populations, Hcy levels are important not only for cardiovascular disease, obesity, and renal disease, but the most interesting evidence concerns study of elevated levels of Hcy in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Finally, a focus on the principal pathologies of the elderly (cardiovascular and neurodegenerative disease, osteoporosis and physical function) is presented. The metabolism of Hcy is influenced by B vitamins, and Hcy-lowering vitamin treatments have been proposed. However, clinical trials have not reached a consensus about the effectiveness of vitamin supplementation on the reduction of Hcy levels and improvement of pathological condition, especially in elderly patients with overt pathologies, suggesting that other dietary and non-dietary factors are involved in high Hcy levels. The importance of novel experimental designs focusing on intra-individual variability as a complement to the typical case-control experimental designs and the study of interactions between different factors it should be emphasized.
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Colorectal polyp risk is linked to an elevated level of homocysteine.
Sun, M, Sun, M, Zhang, L, Shi, S
Bioscience reports. 2018;(2)
Abstract
Several studies have reported an association between levels of folate, homocysteine, and vitamin B12 and the risk of colorectal polyps. Here, our aim is to examine the possible effect of folate, homocysteine, and vitamin B12 levels on the risk of colorectal polyps by means of meta-analysis based quantitative synthesis. According to our inclusion/exclusion criteria, a total of 13 case-control studies were enrolled. The P-value of the association test, standard mean difference (SMD), and 95% confidence interval (CI) were calculated. Pooled analysis data showed a negative correlation between the risk of colorectal polyps and the levels of serum folate, red blood cell (RBC) folate, or vitamin B12 (all P>0.05). Nevertheless, for homocysteine level, we also observed a statistically significant difference between cases and controls in the overall and subgroup analysis of hospital-based control (HB), population-based control (PB), Chinese, Caucasian, or Asian (all P<0.05, SMD > 0). We found that increased levels of homocysteine may be statistically and significantly related to the risk of colorectal polyps.
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Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies.
Oussalah, A, Levy, J, Filhine-Trésarrieu, P, Namour, F, Guéant, JL
The American journal of clinical nutrition. 2017;(4):1142-1156
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Abstract
Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions.Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease.Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition.Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): -0.445 (95% CI: -0.673, -0.217; P < 0.001); I2 = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I2 = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease.Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504.
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Homocysteine: A Potential Common Route for Cardiovascular Risk and DNA Methylation in Psoriasis.
Wang, WM, Jin, HZ
Chinese medical journal. 2017;(16):1980-1986
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Abstract
OBJECTIVE Homocysteine is a sulfur-containing amino acid with potential clinical significance. Abnormal homocysteine levels have been found in patients with psoriasis. This review summarizes the possible correlations among homocysteine, cardiovascular risk, and DNA methylation in psoriasis. DATA SOURCES We retrieved the articles published in English from the PubMed database up to January 2017, using the keywords including "psoriasis," "homocysteine," "cardiovascular risk," "DNA methylation," "methylenetetrahydrofolate reductase," "MTHFR," and "MTHFR C677T." STUDY SELECTION Articles about the roles of homocysteine in the cardiovascular risk and DNA methylation in psoriasis were obtained and reviewed. RESULTS Observational studies consistently reported that elevated homocysteine is an independent risk factor for cardiovascular diseases. Several studies also consistently reported an association between psoriasis and increased cardiovascular risk. A substantial body of evidence also suggested that an elevated homocysteine level is related to the demethylation of DNA. Data from clinical trials also demonstrated that MTHFR C677T polymorphisms as well as DNA methylation aberrations are associated with psoriasis. CONCLUSIONS This review highlighted the relationships among homocysteine, cardiovascular risk, and DNA methylation, suggesting that homocysteine may be a biological link between cardiovascular risk and DNA methylation in psoriasis.
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Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Zhang, Q, Li, S, Li, L, Li, Q, Ren, K, Sun, X, Li, J
Nutrients. 2016;(12)
Abstract
The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation of B-group vitamins or folic acid. A literature search was conducted in PubMed, EmBase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) reporting the concentration of serum Hcy in metformin-treated adults. Meta-analysis was applied to assess the association between metformin and the changes of Hcy concentration. Twelve publications were included in this study. In the overall analysis, metformin administration was not statistically associated with the change of Hcy when compared with the control treatment (mean difference (MD), 0.40 μmol/L; 95% confidence interval (CI), -0.07~0.87 μmol/L, p = 0.10). In the subgroup analysis, metformin was significantly associated with an increased concentration of Hcy in the absence of exogenous supplementation of folic acid or B-group vitamins (MD, 2.02 μmol/L; 95% CI, 1.37~2.67 μmol/L, p < 0.00001), but with a decreased concentration of serum Hcy in the presence of these exogenous supplementations (MD, -0.74 μmol/L; 95% CI, -1.19~-0.30 μmol/L, p = 0.001). Therefore, although the overall effect of metformin on the concentration of serum Hcy was neutral, our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given.
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Homocysteine and Mild Cognitive Impairment: Are These the Tools for Early Intervention in the Dementia Spectrum?
Ansari, Z
The journal of nutrition, health & aging. 2016;(2):155-60
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Abstract
Dementia, being a neurodegenerative disease, has devastating consequences not just for the ailing but also for the carers as it has a tremendous negative impact on the quality of life. The pathophysiology of dementia commences far earlier than its diagnosis. Mild cognitive impairment (MCI) is a stage prior to definite dementia. The progression from MCI to dementia is insidious with no definite demarcation, thus making diagnosis clinically difficult at an early stage. This paper attempts to throw light on the epidemiology, risk factors and the aetiopathogenesis of MCI. It further attempts to elaborate on the rate of conversion of MCI to definite dementia and the factors influencing the same. Many established as well as probable, modifiable as well as non-modifiable risk factors influence the progress of MCI to definite dementia. Homocysteine, a sulphur containing amino-acid has been identified as a probable risk factor for the dementia spectrum. Various existing clinical evidences and biological plausibility towards probable link between homocysteine and dementia are discussed in this paper. B vitamin mediated homocysteine reduction and cognitive outcomes demonstrate mixed results. This review attempts to evaluate hyperhomocysteinaemia and MCI as a brain risk marker and assess their potential for future research with a view to attempt early intervention.
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What do we know about homocysteine and exercise? A review from the literature.
Maroto-Sánchez, B, Lopez-Torres, O, Palacios, G, González-Gross, M
Clinical chemistry and laboratory medicine. 2016;(10):1561-77
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Abstract
High total homocysteine (tHcy) concentrations contribute to an increased risk of cardiovascular diseases and neurodegenerative disorders. Several investigations have focused on the effect of exercise on tHcy concentrations, but results remain controversial. The differences among the methodologies in the investigations make difficult the interpretation of results. This review differentiates the effects of exercise on tHcy and establishes the relation with the implicated biomarkers on tHcy metabolism related to exercise. The electronic database MEDLINE (http://www.ncbi.nlm.nih.gov) was used for searching studies published between years 2002 and 2015. 'Homocysteine', 'Training ', 'Exercise', 'Physical Activity' as well as combinations out of these terms were entered in the database. Articles were grouped in: 1) Acute effect of exercise on tHcy, 2) chronic exercise and tHcy, 3) relationship of physical activity (PA) level and cardiorespiratory fitness with tHcy, and 4) biomarkers related to tHcy and exercise. From a total of 30 articles, most of the studies analyzing the acute effect of exercise showed an increase on tHcy concentrations. Studies analyzing the chronic effect on tHcy concentrations showed contradictory results and no consensus exists probably due to the differences in the methodology, exercise interventions and participants characteristics. Low cardiorespiratory fitness seems to be associated with high tHcy; in contrast, the relation of PA levels and tHcy needs further research. Regarding biomarkers related to tHcy and exercise, some studies showed an increase of folate, vitamin B12, and creatine after acute exercise that could to be due to requirement of protein turnover and an increased metabolic demand of vitamin-B.
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The effect of folate fortification on folic acid-based homocysteine-lowering intervention and stroke risk: a meta-analysis.
Zeng, R, Xu, CH, Xu, YN, Wang, YL, Wang, M
Public health nutrition. 2015;(8):1514-21
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Abstract
OBJECTIVE Folate and vitamin B12 are two vital regulators in the metabolic process of homocysteine, which is a risk factor of atherothrombotic events. Low folate intake or low plasma folate concentration is associated with increased stroke risk. Previous randomized controlled trials presented discordant findings in the effect of folic acid supplementation-based homocysteine lowering on stroke risk. The aim of the present review was to perform a meta-analysis of relevant randomized controlled trials to check the how different folate fortification status might affect the effects of folic acid supplementation in lowering homocysteine and reducing stroke risk. DESIGN Relevant randomized controlled trials were identified through formal literature search. Homocysteine reduction was compared in subgroups stratified by folate fortification status. Relative risks with 95 % confidence intervals were used as a measure to assess the association between folic acid supplementation and stroke risk. SETTING The meta-analysis included fourteen randomized controlled trials, SUBJECTS A total of 39 420 patients. RESULTS Homocysteine reductions were 26·99 (sd 1·91) %, 18·38 (sd 3·82) % and 21·30 (sd 1·98) %, respectively, in the subgroups without folate fortification, with folate fortification and with partial folate fortification. Significant difference was observed between the subgroups with folate fortification and without folate fortification (P=0·05). The relative risk of stroke was 0·88 (95 % CI 0·77, 1·00, P=0·05) in the subgroup without folate fortification, 0·94 (95 % CI 0·58, 1·54, P=0·82) in the subgroup with folate fortification and 0·91 (95 % CI 0·82, 1·01, P=0·09) in the subgroup with partial folate fortification. CONCLUSIONS Folic acid supplementation might have a modest benefit on stroke prevention in regions without folate fortification.
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Homocysteine, iron and cardiovascular disease: a hypothesis.
Baggott, JE, Tamura, T
Nutrients. 2015;(2):1108-18
Abstract
Elevated circulating total homocysteine (tHcy) concentrations (hyperhomocysteinemia) have been regarded as an independent risk factor for cardiovascular disease (CVD). However, several large clinical trials to correct hyperhomocysteinemia using B-vitamin supplements (particularly folic acid) have largely failed to reduce the risk of CVD. There is no doubt that a large segment of patients with CVD have hyperhomocysteinemia; therefore, it is reasonable to postulate that circulating tHcy concentrations are in part a surrogate marker for another, yet-to-be-identified risk factor(s) for CVD. We found that iron catalyzes the formation of Hcy from methionine, S-adenosylhomocysteine and cystathionine. Based on these findings, we propose that an elevated amount of non-protein-bound iron (free Fe) increases circulating tHcy. Free Fe catalyzes the formation of oxygen free radicals, and oxidized low-density lipoprotein is a well-established risk factor for vascular damage. In this review, we discuss our findings on iron-catalyzed formation of Hcy from thioethers as well as recent findings by other investigators on this issue. Collectively, these support our hypothesis that circulating tHcy is in part a surrogate marker for free Fe, which is one of the independent risk factors for CVD.