Influence Homocysteine Levels Research Articles

Serum/plasma homocysteine levels in patients with systemic lupus erythematosus: a systematic review and meta-analysis.

Published studies have shown contradictory results in the association of serum/plasma levels of homocysteine (HCY) with systemic lupus erythematosus (SLE). This study is to systematically evaluate the association of serum/plasma HCY levels in SLE. A search was done using PubMed, Embase, Web of Science, and ScienceDirect databases up to 7 April 2019. Thirty-six articles including 2919 SLE patients and 3120 healthy controls were finally included in this meta-analysis. The HCY levels were significantly higher in SLE patients than in healthy controls (P < 0.001). The subgroup analysis revealed that Asian, African, Arab, Mixed, White and others as well as ages (< 35 and ≥ 35) had significant higher HCY levels in SLE patients than in the healthy controls. The study indicated that patients with disease activity index scores < 8 (P < 0.001) and ≥ 8 (P = 0.003) of SLE had significant higher HCY levels as compared with the healthy controls. It was also revealed that disease duration in SLE patients for < 10 and ≥ 10years (P < 0.001) had significant higher HCY levels as compared with the healthy controls. A significant higher HCY level for body mass index (< 23 and ≥ 23) was found as well as measurement type in SLE patients than healthy controls. This meta-analysis demonstrated higher HCY levels in patients with SLE than healthy controls, suggesting a possible role of HCY in the disease.Key Points• Homocysteine (HCY) is closely related to the mechanisms of systemic lupus erythematosus (SLE).• This study reveals a significant correlation between HCY levels and the various indexes of disease activity.• This study reveals that medication may influence HCY levels in SLE.• This study also discovers that the subgroup analysis of all the factors influences the HCY levels in SLE patients.

The Effects of Plasma Homocysteine in PCOS Women: A Review

Homocysteine is an intermediate substance formed during the breakdown of the amino acid methionine and may undergo remethylation to methionine or trans-sulfuration to cystathionine or cysteine. The metabolism occurs via two pathways: remethylation to methionine, which requires folate and vitamin B12; and transsulfuration to cystathionine, which requires pyridoxal-5’-phosphate. The disturbances in the metabolic pathways lead to the accumulation of Hcy, either by insufficient transsulfuration (through CBS mutations or vitamin B6 deficiency) or by a blockage of remethylation. In the latter case, folate or vitamin B12 deficiency may be involved, as well as MTHFR. High levels of Hcy induce sustained injury of arterial endothelial cells, proliferation of arterial smooth muscle cells and enhance activity of key participants in vascular inflammation, atherogenesis, and vulnerability of the established atherosclerotic plaque. Hyperhomocysteinemia has become the topic of interest in recent years. It has been highly associated with increased risk for cardiovascular disorders, such as, atherosclerosis, thromboembolism and dyslipidemia. Women with PCOS show constellation of metabolic syndromes. Obesity, hyperandrogenemia and type 2 diabetes mellitus is the hallmark of PCOS which later becomes the risk factors for cardiovascular disease. Various studies had revealed the presence of increased Hcy level in PCOS women which may or may not be associated with other biochemical parameters. Intense treatment for PCOS can influence homocysteine levels.

Neuro-fuzzy model of homocysteine metabolism.

In view of well-documented association of hyperhomocysteinaemia with a wide spectrum of diseases and higher incidence of vitamin deficiencies in Indians, we proposed a mathematical model to forecast the role of demographic and genetic variables in influencing homocysteinemetabolism and investigated the influence of life style modulations in controlling homocysteine levels. Total plasma homocysteine levels were measured in fasting samples using reverse phase HPLC. Multiple linear regression (MLR) and neuro-fuzzy models were developed. The MLR model explained 64% variability in homocysteine, while the neurofuzzy model showed higher accuracy in predicting homocysteine with a mean absolute error of 0.00002 μmol/L. Methylene tetrahydrofolate reductase (MTHFR) C677T, 5-methyltetrahydrofolate homocysteine methyltransferase (MTR) A2756G and 5- methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR) A66G were shown to be positively associatiated with homocysteine, while nonvegetarian diet, serine hydroxymethyltransferase 1 (SHMT1) C1420T and TYMS 5'-UTR 28 bp tandem repeat exhibited negative association with homocysteine. The protective role of SHMT1 C1420T was attributed to more H-bonding interactions in the mutant modelled compared to the wild type, as shown through in silico analysis. To conclude, polymorphisms in genes regulating remethylation of homocysteine strongly influence homocysteine levels. The restoration of one-carbon homeostasis by SHMT1 C1420T or increased flux of folate towards remethylation due to TYMS 5'-UTR 28 bp tandem repeat or nonvegetarian diet can lower homocysteine levels.

Associations Between Methylenetetrahydrofolate Reductase Polymorphisms, Serum Homocysteine Levels, and Incident Cortical Cataract.

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels; homocysteine has been implicated as a cataractogenic stressor. To investigate the associations of MTHFR polymorphisms and serum homocysteine levels with incident cortical cataract in an older population. From 1992 to 1994, a population-based cohort study, the Blue Mountains Eye Study, was conducted with 3654 residents (82.4% of eligible participants) of the Blue Mountains region aged 49 years and older. At the second (1997-1999, 5-year follow-up) and third (2002-2004, 10-year follow-up) surveys, 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were examined, respectively. For this report, the second survey serves as baseline when homocysteine levels were assessed, and 5-year incidence of cataract refers to incidence estimated from the second to the third survey. After excluding participants with no follow-up data or DNA or who had previous cortical cataract or cataract surgery, 757 participants were included in gene and environment analyses. This current project on associations with cataract was designed initially March 19, 2013, and completed April 14, 2014. Cataract was assessed using the Wisconsin Cataract Grading system. Two MTHFR polymorphisms, C677T (rs1801133) and A1298C (rs1801131), were included. Serum homocysteine levels were assessed following standard methods. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals for incident cortical cataract, after adjusting for age, sex, smoking status, hypertension, diabetes, education, and myopia. Path analysis was performed to explore a possible pathway of MTHFR polymorphisms via homocysteine levels to cortical cataract. The mean (SD) age of the 1726 participants in the Blue Mountains Eye Study 2 cohort with normal homocysteine levels was 68.3 (8.1) years and 73.2 (8.5) years for those with elevated homocysteine levels. Both the C677T polymorphism (CT/TT vs CC: OR = 1.50; 95% CI = 1.01-2.23) and elevated homocysteine levels (>15 µmol/L: OR = 2.24; 95% CI = 1.38-3.63) were independently associated with increased risk of cortical cataract. Path analysis showed that the genetic effect on cortical cataract was partially mediated via homocysteine levels. Combined CT/TT genotypes and elevated homocysteine levels were associated with a 3-fold risk of cortical cataract (OR = 3.74; 95% CI = 1.79-7.80). The synergy index of both exposures was 1.34 (95% CI = 0.44-4.01). MTHFR polymorphism and elevated homocysteine levels contributed separately and jointly to increased risk of cortical cataract. If these findings are confirmed, homocysteine levels may be a therapeutic target to reduce risk of cortical cataract in persons carrying genetic risk.

Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism.

Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gt mice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.

Homocysteine metabolism in polycystic ovary syndrome

Homocysteine, a sulfur-containing amino acid formed during the metabolism of methionine, exert cytotoxic effects on vascular endothelium. Molecular mechanisms of homocysteine-induced cellular dysfunction include increased inflammatory cytokine expression, altered nitric oxide bioavailability, induction of oxidative stress, activation of apoptosis and defective methylation. Hyperhomocysteinemia is associated with an increased risk of atherosclerotic and thromboembolic disorders, as well as hyperinsulinemia and may partially account for increased risk of cardiovascular disease associated with insulin resistance. Women with PCOS are more likely to develop components of the metabolic syndrome such as disturbances of carbohydrate metabolism, obesity, hypertension and dyslipidemia, which in turn are risk factors for cardiovascular disease. A number of studies confirmed the presence of increased serum homocysteine concentration in PCOS patients and the possible determinants of this observation are still debated. PCOS treatment options can influence homocysteine levels.

The 894G &gt; T (Glu298Asp) Variant in the Endothelial NOS Gene and MTHFR Polymorphisms Influence Homocysteine Levels in Patients with Cognitive Decline

The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer's disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G>T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels (P<0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes (P=0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline.

Plasma Homocysteine Is Not Associated With HIV Serostatus or Antiretroviral Therapy in Women

The effects of HIV serostatus and combination antiretroviral therapy (cART) on plasma homocysteine (HCY) are uncertain. Plasma HCY was assayed in a cross-sectional study of 249 HIV-infected and 127 HIV-uninfected women at the Bronx Women's Interagency HIV Study site. Mean plasma HCY was 7.42 +/- 2.68 in HIV-infected women and 7.18 +/- 2.66 mumol/L in HIV-uninfected women (P = 0.40). Hyperhomocysteinemia (defined as HCY >10 mumol/L) was seen in 16.9% and 13.4% of HIV-infected and HIV-uninfected women, respectively (P = 0.45). Among HIV-infected women, cART use was not associated with HCY level. Compared with the lowest quartile, women with HCY in the highest quartile had lower mean serum vitamin B12 and RBC folate levels. In multivariate analysis that did not include micronutrient levels, age, serum creatinine, and lower CD4% were significantly associated with plasma HCY level in HIV-infected women. Plasma HCY was not associated with HIV serostatus or use of cART in this cross-sectional study. Reduced availability of folate cofactors for HCY remethylation in HIV-infected women with lower folate intake and decreased health status may influence HCY levels.

Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats

Deficiency in nutritional determinants of homocysteine (HCY) metabolism, such as vitamin B(12) and folate, during pregnancy is known to influence HCY levels in the progeny, which in turn may exert adverse effects during development, including liver defects. Since short hypoxia has been shown to induce tolerance to subsequent stress in various cells including hepatocytes, and as vitamins B deficiency and hypoxic episodes may simultaneously occur in neonates, we aimed to investigate the influence of brief postnatal hypoxia (100% N(2) for 5 min) on the liver of rat pups born from dams fed a deficient regimen, i.e., depleted in vitamins B(12), B(2), folate, and choline. Four experimental groups were studied: control, hypoxia, deficiency, and hypoxia + deficiency. Although hypoxia transiently stimulated HCY catabolic pathways, it was associated with a progressive increase of hyperhomocysteinemia in deficient pups, with a fall of cystathionine beta-synthase activity at 21 days. At this stage, inducible NO synthase activity was dramatically increased and glutathione reductase decreased, specifically in the group combining hypoxia and deficiency. Also, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio. In parallel, early exposure to the methyl-deficient regimen induced oxidative stress and led to hepatic steatosis, which was found to be more severe in pups additionally exposed to hypoxia. In conclusion, brief neonatal hypoxia may accentuate the long-term adverse effects of impaired HCY metabolism in the liver resulting from an inadequate nutritional regimen during pregnancy, and our data emphasize the importance of early factors on adult disease.

Novel Genomic Loci Influencing Plasma Homocysteine Levels

Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites. Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63+/-10 years, 70% women) and 964 non-Hispanic whites (61+/-7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach. Mean (+/-SD) homocysteine levels were 10.4+/-5.27 mumol/L in blacks and 10.0+/-2.84 micromol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h2=0.70) and in non-Hispanic whites (h2=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds> or =3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13). Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.

Homocysteine, estrogen and cognitive decline

Background Factors that contribute to cognitive decline in women from midlife remain poorly understood. There are circumstantial data indicating a positive association between homocysteine and cognitive decline and that endogenous and exogenous estrogen may influence homocysteine levels. The aim of this review was to establish what is known of the relationships between cognitive change and homocysteine levels, and the impact of the menopause transition and exogenous estrogen on homocysteine levels.Methods We reviewed the recent published literature from 1993 to 2005 pertaining to the current understanding of the relationship(s) between plasma homocysteine levels and cognitive functioning and endogenous hormone levels and exogenous estrogen use in women.Results Hyperhomocysteinemia is consistently associated with cognitive decline. Dietary supplementation with vitamins may assist in normalizing homocysteine levels; however, there is no evidence that this results in favorable effects on cognition. Changes in endogenous estrogen levels are inversely associated with changes in serum homocysteine. Consistent with this, estrogen therapy is associated with reductions in plasma homocysteine, with the greatest effects reported in women with higher levels of homocysteine at baseline. Limited data indicate that tibolone is associated with little change in homocysteine. The use of raloxifene, the most studied selective estrogen receptor modulator, is associated with a modest reduction in homocysteine.Conclusions There are data to suggest an underlying link between homocysteine levels and cognitive decline. There is also evidence for a link between both the menopause transition and use of exogenous estrogen therapy and homocysteine levels. Clinical data do not support a role for exogenous estrogen in the prevention of dementia in older women; however, the ‘window of opportunity’ theory suggests that there is a need for randomized controlled trials to evaluate the role of estrogen in the early postmenopausal years to protect against cognitive decline in later life.

Homocysteine in assisted reproduction: Does oestradiol influence homocysteine levels?

SummarySteroid hormones including oestradiol have been identified as non-genetic factors that may influence plasma homocysteine. In advanced assisted reproduction, plasma oestradiol levels fluctuate markedly during the treatment cycle starting with normal followed by sub- and then supra-physiological levels. Because of the diverse harmful effects that hyperhomocysteinaemia has been associated with, it is imperative to understand how it may be manipulated during assisted reproduction.A total of 30 women undergoing treatment for infertility were recruited and followed through an advanced assisted reproduction cycle. Blood samples were analysed for oestradiol, homocysteine, vitamin B12, red cell folate and plasma folate during each phase.All patients had normal vitamin B12 and folate levels. Predictably, oestradiol showed marked changes as patients progressed through each treatment phase. However, there were no corresponding significant fluctuations in plasma homocysteine.Oestradiol concentration does not influence plasma homocysteine in women with normal vitamin B12 and folate levels undergoing advanced assisted reproduction.

Vitamin B12 decreases, but does not normalize, homocysteine and methylmalonic acid in end-stage renal disease: A link with glycine metabolism and possible explanation of hyperhomocysteinemia in end-stage renal disease

The genetic and environmental factors influencing catabolism of homocysteine in end-stage renal disease (ESRD) patients remain poorly understood. This study investigated how genetic and nutritional influences affect the response to high-dose vitamin B12 and folate treatment in ESRD patients with hyperhomocysteinemia. We studied 81 hemodialysis patients with hyperhomocysteinemia (> 16 μmol/L) on varied doses of a multivitamin containing 1 mg of folic acid per day. After screening blood work, all patients were switched to daily multivitamin therapy including 1 mg of folic acid for 4 weeks. Vitamin B12, 1 mg/d, was added for an additional 4 weeks. Patients were then randomized to receive folic acid or placebo. The influence of the 3 methylenetetrahydrofolate reductase (MTHFR) 677 C→T genotypes on the efficacy of vitamin therapy was assessed. In addition, we investigated how the metabolic complications of ESRD, including the relationship between methylmalonic acid (MMA) and circulating glycine, may contribute to hyperhomocysteinemia. There was no significant difference in total homocysteine (tHcy) levels between the MTHFR 677 C→T genotypes during the screening phase of the trial. Treatment with a daily multivitamin containing 1 mg folate significantly lowered tHcy levels in all patients by 19.2%. Further supplementation with 1 mg vitamin B12 resulted in greater tHcy reduction among subjects with the MTHFR 677 T/T genotype (P<.01, T/T v C/C or C/T) while lowering MMA equally in all MTHFR genotypes. There was a significant positive correlation between plasma glycine levels and MMA (P <.05). High-dose vitamin therapy significantly lowers, but does not normalize, MMA and tHcy levels. The MTHFR genotype, while influencing homocysteine levels, was not responsible for the majority of the elevation in plasma tHcy. Copyright 2003, Elsevier Science (USA). All rights reserved.

Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland.

Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype. Under a case-control design we compared fasting levels of homocysteine and MTHFR genotypes in groups of subjects consisting of stroke, vascular dementia (VaD), and Alzheimer disease patients and normal controls from Northern Ireland. A significant increase in plasma homocysteine was observed in all 3 disease groups compared with controls. This remained significant after allowance for confounding factors (age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures). MTHFR genotype was not found to influence homocysteine levels, although the T allele was found to increase risk for VaD and perhaps dementia after stroke. We report that moderately high plasma levels of homocysteine are associated with stroke, VaD, and Alzheimer disease. This is not due to vascular risk factors, nutritional status, or MTHFR genotype.

Single nucleotide polymorphisms in the transcobalamin gene: relationship with transcobalamin concentrations and risk for neural tube defects.

Homocysteine levels are elevated in mothers of neural tube defect (NTD) children, which may be due to a disturbed folate or vitamin B12 metabolism. Vitamin B12 is transported to the tissues by transcobalamin (TC). We previously showed that a low holo-TC/total-TC ratio is a risk factor for NTD, possibly due to an impaired binding of vitamin B12 to TC. The coding region of the TC gene of 12 individuals was analysed for genetic variations responsible for a disturbed vitamin B12 binding. The influence of the genetic variations observed on total-TC, holo-TC, holo-TC/total-TC, erythrocyte vitamin B12, plasma homocysteine concentrations and risk for NTD was explored in 42 mothers of a child with NTD and in 73 female controls. Direct sequencing analyses revealed five single nucleotide polymorphisms (SNPs). Three SNPs affected total-TC concentrations, whereas two SNPs seem to affect the binding of vitamin B12. None of the genotypes defined by the SNPs had a significant effect on homocysteine levels, or was associated with an increased NTD risk. Among the five SNPs observed only P259R could partly explain the reduced proportion of vitamin B12 bound to TC, which has been associated with an increased risk for having a child with NTD. Some of the variants studied affected total-TC and holo-TC/total-TC ratio but a larger study population is required to elucidate whether these SNPs influence delivery of vitamin B12 to the tissue, influence homocysteine levels and whether they are associated with an increased NTD risk.

E Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

e Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia