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1.
MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.
Huang, X, Qin, X, Yang, W, Liu, L, Jiang, C, Zhang, X, Jiang, S, Bao, H, Su, H, Li, P, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):679-685
Abstract
OBJECTIVE This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.
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2.
Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers.
Wang, B, Wu, H, Li, Y, Ban, Q, Huang, X, Chen, L, Li, J, Zhang, Y, Cui, Y, He, M, et al
The British journal of nutrition. 2018;(10):1122-1130
Abstract
We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 μmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 μmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60-<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.
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3.
Homocysteine and all-cause mortality in hypertensive adults without pre-existing cardiovascular conditions: Effect modification by MTHFR C677T polymorphism.
Xu, B, Kong, X, Xu, R, Song, Y, Liu, L, Zhou, Z, Gu, R, Shi, X, Zhao, M, Huang, X, et al
Medicine. 2017;(8):e5862
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Abstract
BACKGROUND Previous studies support an association between elevated total homocysteine (tHcy) levels and increased all-cause mortality. However, few prospective studies have examined this association in hypertensive patients, and/or tested any effect modification by the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. METHODS This was a post hoc analysis of the China Stroke Primary Prevention Trial. Serum tHcy and folate were measured at baseline. Individual MTHFR C677T genotype (CC, CT, and TT) was determined. Evidence for death included death certificates or home visits. Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan-Meier method, and group differences were compared by log-rank tests. Hazard ratios (HRs) and 95% confidence intervals were estimated by Cox proportional-hazard regression models, adjusting for age, sex, baseline folate, vitamin B12, blood pressure, body mass index, smoking and alcohol drinking status, study center, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, creatinine, and treatment group. Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested. RESULTS The analyses included 20,424 hypertensive patients (41% males) without a history of myocardial infarction or stroke. Baseline mean age (SD) was 60 ± 7.5 years and mean (SD) serum tHcy was 14.5 ± 8.4 μmol/L. After a mean follow-up period of 4.5 years, there were 612 (3%) all-cause deaths. Kaplan-Meier survival curves revealed a graded relationship between tHcy quartiles and all-cause mortality. The HRs, using the lowest quartile as the reference, were 1.2, 1.2, and 1.5 in Q2, Q3, and Q4, respectively. A linear trend test, using natural log-transformed tHcy, resulted in an HR of 1.5 (95% confidence interval 1.2-1.9, P < .001) after adjustment for lifestyle and health-related variables. Whereas the MTHFR genotype alone had little effect on mortality, it significantly modified the tHcy-mortality association, which was much stronger in the CC/CT genotype than in the TT genotype (P for interaction < 0.05). CONCLUSIONS Among Chinese hypertensive patients without cardiovascular comorbidities, elevated tHcy was a significant risk marker for death from all causes, and the association was subject to effect modification by MTHFR genotypes. If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention.
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Plasma Homocysteine and Prognosis of Acute Ischemic Stroke: a Gender-Specific Analysis From CATIS Randomized Clinical Trial.
Zhong, C, Xu, T, Xu, T, Peng, Y, Wang, A, Wang, J, Peng, H, Li, Q, Geng, D, Zhang, D, et al
Molecular neurobiology. 2017;(3):2022-2030
Abstract
Elevated total homocysteine level (tHcy) has been hypothesized to be associated with morbidity and mortality of stroke; however, results regarding the association between plasma tHcy status and prognosis of acute ischemic stroke are inconsistent. Moreover, the gender effect on this association has yet to be explored. We thus prospectively investigated whether higher tHcy concentrations predicted poor stroke prognosis in Chinese adults. A total of 3309 acute ischemic stroke patients were included in this prospective multicenter study from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Baseline tHcy concentrations were quantitatively determined via enzymatic cycling assay. The primary outcome was a combination of death and major disability at 3 months (modified Rankin scale scores 3-6) after hospitalization. Multivariate logistic regression models with restricted cubic splines were used to determine the association between baseline plasma tHcy and the subsequent outcome. Higher plasma tHcy concentrations were associated with increased risks of the primary outcome in women but not in men (P interaction = 0.016). Adjusted odds ratios comparing two extreme tHcy quartiles were 1.83 (95 % confidence interval 1.12-2.98; P trend = 0.02) in women and 0.87 (95 % confidence interval 0.61-1.25; P trend = 0.37) in men. The significant association between baseline tHcy status and stroke prognosis in women, but not in men, persisted in further subgroup analyses, stratified by age, baseline systolic blood pressure, and other pre-specified factors. Elevated tHcy is positively associated with poor prognosis of acute ischemic stroke in women, but not in men. Further studies are needed to replicate our findings and to clarify the potential sex-specific mechanisms.
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5.
Association between percent decline in serum total homocysteine and risk of first stroke.
Huang, X, Li, Y, Li, P, Li, J, Bao, H, Zhang, Y, Wang, B, Sun, N, Wang, J, He, M, et al
Neurology. 2017;(20):2101-2107
Abstract
OBJECTIVE To examine whether a change in serum total homocysteine (tHcy) levels is associated with first stroke risk in a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT). METHODS We analyzed 16,867 participants of the CSPPT with tHcy measurements at both baseline and exit visits. The primary outcome was first stroke. The secondary outcome was a composite of cardiovascular events consisting of cardiovascular death, myocardial infarction, and stroke. The percent decline in tHcy was calculated as [(baseline tHcy - exit tHcy)/baseline tHcy × 100]. RESULTS Over the median treatment duration of 4.5 years, participants who developed a first stroke had a significantly lower percent decline in tHcy (β = -5.7; 95% confidence interval [CI] -8.8 to -2.6) compared to their counterparts. A 20% tHcy decline was associated with a reduction in stroke risk of 7% (hazard ratio [HR] 0.93; 95% CI 0.90-0.97). When percent decline in tHcy was assessed as tertiles, a significantly lower stroke risk was found in those in tertiles 2-3 (HR 0.79; 95% CI 0.64-0.97) compared with participants in tertile 1. Similar results were observed for the composite of cardiovascular events. The beneficial effect associated with greater tHcy reduction was observed across strata for age, sex, treatment group (with vs without folic acid), MTHFR C677T genotypes, baseline tHcy and serum folate levels, and blood pressure control. CONCLUSIONS Percent lowering in tHcy was significantly associated with a reduction in first stroke risk in Chinese adults with hypertension, and if further confirmed, may serve as a useful indicator for folic acid treatment efficacy on stroke prevention. CLINICALTRIALSGOV IDENTIFIER NCT00794885.
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Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients.
Qin, X, Li, Y, Sun, N, Wang, H, Zhang, Y, Wang, J, Li, J, Xu, X, Liang, M, Nie, J, et al
Arteriosclerosis, thrombosis, and vascular biology. 2017;(1):166-172
Abstract
OBJECTIVE We aimed to examine whether baseline homocysteine (Hcy) concentrations affect antihypertensive responses to enalapril treatment among previously untreated hypertensive patients (n=10 783) in the CSPPT (China Stroke Primary Prevention Trial). APPROACH AND RESULTS After a 3-week run-in treatment with a daily dose of 10 mg enalapril, eligible hypertensive patients were randomly assigned to a double-blind daily treatment of a tablet of either enalapril (10 mg) and folic acid (0.8 mg) or enalapril (10 mg) alone for a median of 4.5 years. After the 3-week treatment period with enalapril alone, the systolic blood pressure-lowering effect was significantly reduced by 1.39 (95% confidence interval 0.40-2.37) and 3.25 (95% confidence interval 1.98-4.52) mm Hg, respectively, in those with baseline Hcy concentrations of 10 to 15 and ≥15 μmol/L (P for trend <0.001) as compared with those with Hcy concentration of <10 μmol/L. Similar results were observed after a 15-week treatment period with enalapril alone. After a median 4.5-year enalapril-based antihypertensive treatment period, compared with those with Hcy concentration of <10 μmol/L, the systolic blood pressure-lowering effect was still significantly reduced by 0.77 (95% confidence interval 0.01-1.53) and 1.70 (95% confidence interval 0.72-2.68) mm Hg, respectively, in those with Hcy concentrations of 10 to 15 and ≥15 μmol/L (P for trend <0.001). In addition, participants with higher baseline Hcy concentrations had persistently higher systolic blood pressure levels across the entire study treatment period. Similarly, baseline Hcy concentrations were inversely associated with diastolic blood pressure reduction during the short-term enalapril alone treatment. However, the inverse association between baseline Hcy and diastolic blood pressure reduction was attenuated and became insignificant after the long-term enalapril-based treatment period. CONCLUSIONS Elevated Hcy concentrations significantly decreased the antihypertensive effect of the short-term and long-term enalapril-based antihypertensive treatment in previously untreated hypertensive patients.
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[Clinical studies on fifty-seven Chinese patients with combined methylmalonic aciduria and homocysteinemia].
Zhang, Y, Song, JQ, Liu, P, Yan, R, Dong, JH, Yang, YL, Wang, LF, Jiang, YW, Zhang, YH, Qin, J, et al
Zhonghua er ke za zhi = Chinese journal of pediatrics. 2007;(7):513-7
Abstract
OBJECTIVE Methylmalonic aciduria (MMA) is a common one of the congenital disorders of organic acids metabolism. Some of the patients with the disorder are complicated with homocysteinemia. Recently, gas chromatography-mass spectrometry (GCMS) has been used to diagnose MMA in China. However, the diagnosis of the patients with combined MMA and homocysteinemia is often delayed. In this study, the natural history, clinical features and outcome of 57 Chinese patients with combined MMA and homocysteinemia were investigated. METHODS From 1996 to 2006, 96 MMA patients from 16 provinces or cities were diagnosed in our hospital by urine organic acids analysis using GCMS. Homocysteinemia was found by serum and urine total homocysteine determination using a fluorescence polarization immunoassay. RESULTS Fifty-seven of the 96 MMA patients (59.4%, 32 males and 25 females) were found to have combined MMA and homocysteinemia. They had markedly increased urine methylmalonic acid, total serum homocysteine (81.5 to 226.5 micromol/L vs. normal range 4.5 to 12.4 micromol/L) and urine homocysteine (79.1 to 414.5 micromol/L vs. normal range 1.0 to 25.0 micromol/L). Thirteen (22.8%) of them presented with symptoms resembled hypoxic-ischemic encephalopathy in the neonatal period. Fourteen (24.6%) patients had the onset at the age of one month to 1 year with mental retardation, vomiting and epilepsy. Nine (15.8%) showed developmental delay, seizures, poor appetite or anemia from the age of 1 to 3 years. Eighteen (31.6%) had psycho-motor degeneration at the age of 6 to 15 years. Among them, 7 patients experienced multiple organ dysfunctions with liver dysfunction, hematuria, renal failure and peripheral neuropathy. Three (5.3%) patients developed progressive mental degeneration, motor disorders and anorexia at the ages of 16, 24 and 34 years. Eleven (19.3%) patients ultimately died; 5 (8.8%) of them were diagnosed postmortem. Forty-six (80.7%) patients were treated with vitamin B12, folic acid, L-carnitine and betaine supplementation and 11 (19.3%) of them recovered completely. CONCLUSIONS Combined MMA with homocysteinemia is a common form of MMA in China. The clinical spectrum of the patients varies from severe neonatal-onset forms with high mortality to milder forms with adult-onset. Serum or urine total homocysteine analysis is important for the deferential diagnosis of the patients with MMA.
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8.
Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism.
Hustad, S, Ueland, PM, Vollset, SE, Zhang, Y, Bjørke-Monsen, AL, Schneede, J
Clinical chemistry. 2000;(8 Pt 1):1065-71
Abstract
BACKGROUND Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy concentrations are partly determined by folate, cobalamin, and vitamin B(6) status, and methylenetetrahydrofolate reductase (MTHFR) and other flavoenzymes are important for the biotransformation of these vitamins. This motivates the investigation of the possible relationship between riboflavin status and tHcy. METHODS The study had a cross-sectional design and included 423 healthy blood donors, ages 19-69 years. We determined plasma tHcy, serum folate, serum cobalamin, serum creatinine, and MTHFR C677T genotype. In addition, we measured riboflavin and its two coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, in EDTA plasma by capillary electrophoresis and laser-induced fluorescence detection. RESULTS Riboflavin determined tHcy independently in a multiple linear regression model with adjustment for sex, age, folate, cobalamin, creatinine, and MTHFR genotype (P = 0.008). tHcy was 1.4 micromol/L higher in the lowest compared with the highest riboflavin quartile. The riboflavin-tHcy relationship was modified by genotype (P = 0.004) and was essentially confined to subjects with the C677T transition of the MTHFR gene. CONCLUSIONS Plasma riboflavin is an independent determinant of plasma tHcy. Studies on deficient populations are needed to evaluate the utility of riboflavin supplementation in hyperhomocysteinemia.