Serum tHcy Research Articles

Acute physical exercise increases homocysteine concentrations in young trained male subjects

High levels of homocysteine (Hcy) have been identified as a cardiovascular risk factor. Regarding physical exercise, the results are contradictory. The aim of this study was to determine the influence of maximal intensity exercise and submaximal constant exercise on total serum homocysteine concentrations (tHcy) and other related parameters. Ten physically active male subjects (mean age: 23.51 ± 1.84), performed two treadmill tests, a maximal test and a stable submaximal test at an intensity of 65% of maximal oxygen uptake (VO2max). Serum concentrations of tHcy, Folate, Vitamin B12 and creatinine were analysed before and after each test. Significant increase in serum tHcy concentrations after the maximal (p < 0.05) and submaximal (p < 0.01) tests were observed. Folate and vitamin B12 concentrations also increased significantly after both tests (p < 0.05). Creatinine levels increased only after the maximal test (p < 0.001). A statistically significant inverse relationship was found between folate and tHcy concentrations (p < 0.05) at all the measurement points. THcy levels increased significantly after acute exercise in both maximum and submaximal intensity exercises.

Elevated homocysteine and carotid plaque area and densitometry in the Northern Manhattan Study.

Studies have linked elevated total homocysteine (tHcy) levels to atherosclerotic carotid plaque development, but data are limited to predominantly white populations. We examined the association between tHcy and carotid plaque burden and morphology in a multiethnic cohort. In the Northern Manhattan Study, we conducted a cross-sectional analysis among 1327 stroke-free subjects (mean age, 66 ± 9; 41% men; 19% black; 62% Hispanic; 17% white) with serum tHcy and ultrasonographic assessment of plaque morphology measured by gray-scale median (GSM) and total plaque area (TPA). GSM and TPA were examined in 4 categories. High and low GSM categories were considered echodense and echolucent plaque, respectively, and compared with no plaque. Logistic regression models were used to assess the associations of tHcy with GSM and TPA adjusting for demographics, vascular risk factors, renal insufficiency, and B(12) deficiency. The mean tHcy was 9.4 ± 4.8 µmol/L (median=8.6). The prevalence of carotid plaque was 57% (52% among Hispanics, 58% black, and 70% white). Among those with plaque, the mean TPA was 20.3 ± 20.6 mm(2) (median=13.6) and mean GSM 90.9 ± 28.5 (median=93.0). The top 2 tHcy quartiles (versus quartile 1) had an elevated risk of having either echolucent plaque (tHcy Q3, odds ratio [OR]=1.8; [95% confidence interval {CI} 1.2-2.8]; tHcy Q4, OR=1.9 [95% CI 1.2-3.1]) or echodense plaque (tHcy Q3, OR=1.7 [95% CI, 1.1-2.7]; tHcy Q4, OR=1.9 [95% CI, 1.2-3.2]). The top 2 tHcy quartiles were also more likely to be in the highest TPA category (tHcy Q3, OR=1.8 [95% CI, 1.1-3.0]; tHcy Q4, OR=2.2 [95% CI, 1.3-3.7]). In this population-based multiethnic cohort, elevated tHcy was independently associated with plaque morphology and increased plaque area, subclinical markers of stroke risk.

Association of the C677T Polymorphism in the MTHFR Gene with Risk of Oral Squamous Cell Carcinoma in South Indian Population

Background: The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with reduced enzyme activity, and a significant increase in serum homocysteine (Hcy) concentration. MTHFR C677T polymorphism was likely to play an important role in the susceptibility to OSCC. Methods: In this case-control study, we genotyped 150 OSCC patients and 150 controls, using a PCR-RFLP method. The serum total homocysteine levels were quantitatively detected using commercial enzyme immunoassay (EIA) kits from AxisShied Diagnostics Ltd, UK. Results: In the present study heterozygous CT genotype was found statistically significantly more prevalent in patients than in controls [OR 3.38, 95%CI 146-7.79, p-value 0.004], whereas TT genotype was not statistically significant [OR 2.01, 95%CI 0.18-22.4, p-value 0.05]. CC genotype may be protective for OSCC [OR 0.30, 95%CI 0.13-0.67, P-value 0.003]. The mean serum tHcy levels (mmol/L) 15.0 were higher in cases in all three CC (26.81±7.51), CT (29.26±7.67) and TT (48.85±28.07) genotypes when compared to CC (17.85±2.18), CT (17±1.0) and TT (0) with controls. However, significant variation of homocysteine levels was not observed between the genotypes of OSCC patients and controls. Conclusion: The results of the present study indicate that the frequency of MTHFR 677 ‘T’ allele is rare and CT genotype may be associated with OSCC risk. However, the polymorphisms in the MTHFR gene (677C/T) that are reported to modulate homocysteine levels were not associated with OSCC.

Plasma ω-3 fatty acid levels negatively and ω-6 fatty acid levels positively associated with other cardiovascular risk factors including homocysteine in severe obese subjects.

Obesity and homocysteine (tHcy) are important risk factors for cardiovascular diseases (CVD). Plasma omega-3 fatty acids (ω-3 FAs) and omega-6 fatty acids (ω-6 FAs) are essential fatty acids with diverse biological effects in human health and disease. We have investigated the relation of plasma ω-3 FAs and ω-6 FAs levels with other cardiovascular risk factors including tHcy in severe obese subjects. This study was performed on 96 severe obese and 65 normal weight subjects. Plasma fatty acid composition was measured by GC/MS and serum tHcy level was measured by HPLC methods. There were no differences between groups in terms of concentrations of serum tHcy, plasma ω-3 FAs, ω-6 FAs and ω-3/ω-6 ratio, whereas serum vitamin B-12 (p<0.01) and folic acid (p<0.05) levels were lower than those of the normal weight subjects. Homocysteine positively correlated with ω-6 FAs and negatively correlated with ω-3 FAs in severe obese and normal weight subjects. Serum vitamin B-12 positively correlated with ω-3 FAs (p<0.01) and ω-3/ω-6 ratio (p<0.01) and negatively correlated with ω-6 FAs (p<0.05) in severe obese subjects. Serum folic acid positively correlated with ω-3 FAs (p<0.01) in severe obese subjects. Our results suggest an association between the plasma ω-3 FAs and ω-6 FAs and serum tHcy concentrations in severe obese and normal weight subjects. Low levels vitamin B-12 and folic acid may have been responsible for the elevated tHcy levels in severe obese subjects, increasing the risk for future development of cardiovascular diseases.

High serum total homocysteine levels accelerate hip bone loss in healthy premenopausal women and men

IntroductionDespite extensive evidence demonstrating the direct, detrimental role of homocysteine on bone metabolism, the effects of serum total homocysteine (tHcy) on bone loss are still equivocal. In the present study, we performed a longitudinal study on healthy participants of various ages of both sexes in order to investigate the association between serum tHcy concentrations and annualized changes in bone mineral density (BMD). MethodsA total of 460 Koreans≥30years of age received comprehensive, routine health examinations for an average period of 3years. The BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. ResultsAfter adjusting for potential confounders, the rates of bone loss at the proximal femur sites were significantly accelerated in a dose–response fashion across increasing tHcy concentrations in premenopausal women and men, but not in postmenopausal women. Consistently, compared with subjects in the lowest tHcy quartile, premenopausal women in the third and/or highest tHcy quartile and men in the highest tHcy quartile showed significantly higher rates of bone loss at all proximal femur sites (p=0.015–0.048) and at the total femur and femur neck (p=0.008–0.013), respectively. In contrast, there were no differences in terms of bone loss among the tHcy quartiles for postmenopausal women. ConclusionThese data provide the first clinical evidence that increased tHcy levels could be an independent risk factor for the future deterioration of bone mass in premenopausal women and men.

Traditional Eating Habits and Level of Homocysteine in the Acute First-Ever Ischaemic Stroke

Background: Meal with high-fat content represents a common and increasing habit in general population in the Macedonia. Contribution of homocysteine and meal with high-fat content in the acute phase of first-ever ischaemic stroke (AFIS) due to the different dietary habits remains unclear. Aim: Our aims/hypothesis was comparison of serum total homocysteine (tHcy) level and dietary habits in patients with AFIS and in controls due to non-consuming (non-users) or consuming (users) meat with high content of fats that can be regarded as traditional eating habits influenced by religion dietary restrictions from Lower Pollog populations. Materials and Methods: From initially 847 patients hospitalized from September 2008 to August 2010in neurology department, only 231 patients with diagnostic entity-AFIS and 194 healthy subjects were evaluated in this study. Serum tHcy was measured on admission and dietary history was noted. Results: In the overall pooled estimate, for all included study participants, serum tHcy level in the acute phase of disease and frequency of users are similar in patient with AFIS and in controls, but non-users mostly was dispose to AFIS and hyperhomocysteinemia. Conclusion: Meat with high-fat content is very often combined with tHcy-increasing effects at users. Because the regression coefficient of linear regression model with users as variable, adjusting for age, gender and serum tHcy of patients with AFIS was not confirmed the statistical significance of previous pretesting factors by cross tabulation model our research could not confirm that hyperhomocisteinemia and meat with high-fat content are the only reason for cause of AFIS.

Serum homocysteine and folate concentrations among a US cohort of adolescents before and after folic acid fortification

We assessed serum homocysteine (tHcy) and folate concentrations among US adolescents before and after fortification of cereal-grain products with folic acid, and associations with demographic, behavioural and physiological factors. Observational study conducted among participants of a randomized trial. The Child and Adolescent Trial for Cardiovascular Health (CATCH) study. Adolescents (n 2445) in grades 8 (pre-fortification, mean age 14 years) and 12 (post-fortification, mean age 18 years). Average serum concentrations of tHcy, folate and vitamin B6 increased by 17 %, 16 % and 14 %, respectively, while serum concentrations of vitamin B12 decreased by 11 % post-fortification. Folic acid fortification provided, on average, an additional intake of 118 μg folate/d. Male sex (P < 0.0001) and white race (P = 0.0008) were associated with significantly greater increases in tHcy concentration, while increases in BMI (P = 0.006) and serum folate concentration (P < 0.0001) were associated with significant decreases in tHcy concentration. Female sex (P < 0.0001), non-smoking (P < 0.0001), use of multivitamins (P < 0.0001) and higher dietary intake of folate (P = 0.001) were associated with significantly greater increases in serum folate concentrations. From grade 8 to grade 12, the upward age trend in serum tHcy concentration was uninterrupted in its course (P > 0.50); whereas serum folic acid concentration showed a downward trend that incurred a discrete jump upward (17 % higher; P < 0.0001) with fortification. These trends differed significantly for males v. females (P < 0.001 for interaction). Fortification had a significant impact on improving folate status but not serum tHcy concentrations among US adolescents.

Estimated Creatinine Clearance, Homocysteine and High Sensitivity-C-Reactive Protein Levels Determination for Early Prediction of Nephropathy and Atherosclerosis Risk In Type 2 Diabetic Patients.

Type 2 diabetes mellitus (T2D) patients are increased risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). Many studies had demonstrated that CKD is significantly associated with CVD. We aim to indicate the using estimated creatinine clearance (eCrCl), homocysteine (tHcy), and high sensitivity-C-reactive protein (hs-CRP) levels, may have an impact on the interpretation risk for nephropathy and CVD. eCrCl was using the Cockroft-Gault formula, eCrCl levels were stratified according to the Kidney Disease Outcome Quality Initiative definition. We measured serum tHcy, hs-CRP, and the other biochemical variables in 54 T2D patients compared with 40 age matched healthy controls (NDM). T2D patients were significantly lower eCrCl than NDM (P<0.05). T2D patients also showed significantly higher in tHcy, hs-CRP, and MDA levels than NDM subjects (P<0.05). The eCrCl was significantly correlated with tHcy and hs-CRP levels in T2D patients (r=-0.504, P<0.001; r=-0.282, P=0.047). eCrCl had an impact on interpretation for CKD, especially in T2D patients. Decrease eCrCl concomitant with increased in tHcy, hs-CRP, and MDA levels may present a higher risk for future diabetic nephropathy and CVD.

Serum homocysteine and folate but not vitamin B12 are predictors of CHD mortality in older adults

The associations of serum levels of homocysteine (tHcy), vitamin B(12), and folate with risk of all-cause and coronary heat disease (CHD) mortality is controversial, and the evidence in older adults is limited. The aim of this study was to examine whether serum folate, vitamin B(12), and tHcy independently predict risk of CHD-related and all-cause mortality in older adults. Serum concentrations of folate, vitamin B(12), and tHcy were determined from blood samples obtained from 3010 Blue Mountains Eye Study participants (1997-99), aged ≥55 years. CHD and all-cause mortality was confirmed using the Australian National Death Index. Persons in the highest quartile of serum tHcy had increased risk of CHD mortality compared to those in the lowest quartile (multivariable-adjusted hazard ratio, HR, 2.45, 95% CI 1.30-4.62). A significant continuous association was observed between serum tHcy and CHD mortality (HR per SD ( = 4.8 µmol/l) increase in serum tHcy 1.25, 95% CI 1.08-1.45), after multivariable-adjustment. A significant association between folate deficiency and CHD-mortality was found (multivariable-adjusted HR 1.53, 95% CI 1.01-2.29). Hyperhomocysteinaemia (>15 µmol/l) was a significant predictor of all-cause mortality (multivariable-adjusted HR 1.47, 95% CI 1.18-1.83). A significant interaction was observed between hyperhomocysteinaemia and folate deficiency for all-cause and CHD mortality (p for interaction = 0.03 and p for interaction = 0.05, respectively). Serum tHcy and folate were independent predictors of CHD and all-cause mortality, while vitamin B(12) was not associated. As raised tHcy levels and folate deficiency are associated with poorer lifestyle, changes to a more healthful lifestyle among older adults may minimize the adverse vascular effects of elevated tHcy.

Folate and vitamin B-12 biomarkers in NHANES: history of their measurement and use

NHANES measured folate and vitamin B-12 status biomarkers, starting with serum folate from NHANES I (1974–1975) through 2010. Subsequent NHANES measured additional biomarkers [eg, red blood cell folate, serum vitamin B-12, total homocysteine (tHcy), methylmalonic acid, serum folic acid, and 5-methyltetrahydrofolic acid]. Examples of the uses of these data are wide ranging and include public policy applications, the derivation of reference intervals, and research. Periodically, the National Center for Health Statistics and its federal partners convene expert panels to review the use of the folate- and vitamin B-12–related biomarkers in NHANES. These panels have evaluated the need for results to be comparable across time and with published data and the use of crossover studies and adjustment equations to ensure comparability. With the recent availability of reference methods and materials for serum folate and tHcy, NHANES has started to use traceability approaches to enhance the accuracy and comparability of its results. A major user concern over the years has been the use of cutoffs to estimate the prevalence of inadequate folate and vitamin B-12 status. Because these cutoffs depend on the measurement procedure, several expert panels suggested approaches for dealing with cutoff challenges. This review summarizes the history and use of folate- and vitamin B-12–related biomarkers beginning with NHANES I (1974–1975) through 2010.

Serum total homocysteine and lipoprotein (a) levels in acute myocardial infarction and their response to treatment with vitamins.

To assess the relationship of serum total homocysteine (tHcy) and lipoprotein (a) [Lp(a)] levels with systemic hypertension, Diabetes mellitus and smoking as risk factors in patients with acute myocardial infarction (AMI) and changes in the former levels with vitamins supplementation. An interventional study. Medical College for Women and Hospital (MCW & H), Dhaka, Bangladesh, from July 2008 to December 2009. Consecutive AMI patients were recruited from the Coronary Care Unit (CCU) at MCW &H, Dhaka. Blood samples were collected at inclusion (Patient-I0). They were given conventional treatments and prescribed vitamins (vitamins B6=25 mg, B12=2 mg and folic acid=2.5 mg) daily for 2 months. After follow-up, blood samples were taken again (Patient-II0). A group of 25 normal subjects were also included as controls. Serum tHcy and Lp(a) were measured by kinetic method and nephelometric method respectively. Serum tHcy (μmol/L) and Lp(a) (mg/dl) levels were elevated in Patient-I0 that reduced in Patient-II0 after vitamins supplementation, but not to the normal control level. tHcy of Patient-I0 was 25.1 ± 4.7 μmol/L, of Patient-II0 was 20.1 ± 4.5 μmol/L and of controls 12.1 ± 3.3, p < 0.001. Lp(a) of Patient-I0 was 43.1 ± 15.2 mg/dL, of Patient-II0 was 35.6 ± 10.2 mg/dL, Control: 22.3 ± 5.2 mg/dL, p < 0.001. Elevated tHcy and Lp(a) levels were independent of the traditional risk factors (p > 0.1). However, in a significant proportion of patients tHcy and Lp(a) levels were reduced to control levels (tHcy: p < 0.001, Lp(a): p < 0.01). These results indicated that tHcy and Lp(a) levels were possibly atherogenic risk factors independent of conventional risk factors. Since both tHcy and Lp(a) levels responded in a similar fashion, a common point of the metabolic and pathogenetic pathways of tHcy and Lp(a) may be influenced by the vitamins supplementation.

Physiologic changes in homocysteine metabolism in pregnancy: A longitudinal study in Spain

Objective The aim was to investigate whether pregnancy-induced changes in total homocysteine (tHcy) are associated with folate and vitamin B12 nutritional status, genetic C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) enzyme, and gestation outcome at a time when folic acid supplementation started to be recommended in the Spanish health system. Methods In total 154 pregnant women were recruited from among gynecologic patients of the Alcorcón Public Hospital Outpatient Clinic (Madrid, Spain). Blood tests were performed at weeks 15, 24, and 32 of pregnancy. Total Hcy, folate, and vitamin B12 serum fasting concentrations were measured using an IMx system. Genotype analyses were done by polymerase chain reaction/restriction fragment/length polymorphism analysis. Results Folate and vitamin B12 serum concentrations decreased significantly ( P < 0.01) through pregnancy and reached the lowest values in the third trimester. Serum tHcy concentrations were significantly ( P < 0.01) lower in the second trimester but increased in the third trimester. Frequencies of MTHFR C667T genotype were CC (35.7%), CT (57.2%), and TT (7.1%). Total Hcy concentration was not statistically influenced by maternal genotype. Plasma folate was the single negative predictor of maternal tHcy in the first trimester of pregnancy; 11.1% of gestations resulted in intrauterine growth restriction, 7.9% in gestational diabetes mellitus, and 4.8% in gestational hypertension. No significant differences in serum folate, vitamin B12, or tHcy concentrations were found in complicated pregnancies and these were unrelated to MTHFR genotype. Conclusion Although tHcy seems to be physiologically low in this Spanish population and unrelated to folate and B12 nutritional status, C677T MTHFR genotype, and some pregnancy complications, we support the statement that appropriate folate concentration may be important throughout pregnancy to prevent abnormalities associated with altered status (e.g., neural tube defects). According to our study, supplementation with folic acid seems to achieve this purpose because diet alone may be insufficient. In addition, a poor vitamin B12 status, as measured by plasma levels, may indicate that supplementation of both vitamins is needed.

Relationship Between Genetic Polymorphisms of Methylenetetra hydrofolate Reductase (C677T, A1298C, and G1793A) as Risk Factors for Idiopathic Male Infertility

The human methylenetetrahydrofolate reductase (MTHFR) gene plays a crucial role in folate metabolism. Data regarding the influence of MTHFR gene polymorphisms on male fertility status are scarce and conflicting. We determined associations between 3 MTHFR gene polymorphisms (C677T, A1298C, and G1793A), serum folate, and total homocysteine (tHcy) levels, with male fertility status and semen parameters. MTHFR genotypes were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique and serum tHcy, folate, and vitamin B12 concentrations were measured in 164 men with idiopathic infertility and 328 healthy participants. There was a significant difference in genotype frequency distribution of MTHFR C677T polymorphism between infertile patients and controls (P = .004). The 677T allele carriers (TC or TT) had a significantly increased risk of infertility compared with the CC homozygotes (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.21-2.75, and OR = 2.68, 95% CI = 1.84-3.44, respectively), in a logistic regression model after adjustment for confounding factors. Men with the 677T, 1298C, and 1793G alleles showed significantly higher serum tHcy and lower folate levels (all Ps < .01). We found a positive correlation between serum folate concentrations and sperm density (r = .74, P = .001), percentage of sperm with progressive motility (r = .68, P = .001), as well as percentage of sperm with normal morphology (r = .72, P = .001). MTHFR C677T polymorphism is associated with an increased risk of idiopathic male infertility. Further study on the biologic role that this polymorphism plays in the development of infertility may lead to better understanding of the etiology of impaired spermatogenesis.

Serum asymmetric dimethylarginine (ADMA), homocysteine, vitamin B12, folate levels, and lipid profiles in epileptic children treated with valproic acid

Recent reports have demonstrated elevated serum homocysteine (Hcy) levels in children receiving valproic acid (VPA) therapy. Elevated Hcy levels might play a potential role in the resistance to antiepileptic drugs, and might lead to an increased risk for a vascular disease. It has been reported that elevated total homocysteine (tHcy) levels are associated with elevated asymmetric dimethylarginine (ADMA) levels, which are factors that may be better indicators of endothelial dysfunction compared to serum homocysteine levels, because they are less sensitive to changes, such as fasting status, physical activity, and other factors. In this study, we aim to evaluate serum ADMA, Hcy, lipid, folate, and vitamin B₁₂ levels in epileptic children, receiving VPA monotherapy. Forty-four epileptic children, receiving VPA monotherapy for at least 6 months and 28 healthy children aged between 4 and 16 years, were recruited. Serum lipids, lipoproteins, folate, vitamin B₁₂, Hcy, and ADMA levels were analyzed in both study groups. Serum Hcy, ADMA, and vitamin B₁₂ levels were higher in patients than in controls (p < 0.001 for tHcy and ADMA levels; p < 0.05 for vitamin B₁₂ levels); however, serum lipid, lipoprotein, and folate levels were similar. According to the duration of epilepsy, serum tHcy, ADMA, and triglyceride (TG) levels were higher in patients with epilepsy for ≥ 2 years than in patients with epilepsy for < 2 years (p < 0.001 for serum ADMA levels, p < 0.01 for tHcy levels, and p < 0.05 for serum TG levels). Similarly, with respect to the duration of VPA therapy, serum tHcy, ADMA, and TG levels were higher in patients who had received VPA therapy for more than 2 years (p < 0.001 for serum ADMA levels, p < 0.05 for serum tHcy levels, p < 0.01 for TG levels). Serum ADMA levels were significantly higher in patients receiving VPA at the dose of 25-30 mg/kg/day than in those receiving 20 mg/kg/day (p < 0.01). In conclusion, our study found increased serum ADMA levels and increased tHcy levels in epileptic children receiving VPA monotherapy. Increased serum ADMA levels were demonstrated in epileptic children who have had a seizure history greater than 2 years, and have used VPA therapy for more than 2 years, and have received higher doses of VPA. Routine monitoring of serum ADMA and tHcy levels might have beneficial effects for patients receiving long-term VPA therapy, especially in children who have other potential risk factors for vascular diseases. Further studies are needed to investigate serum ADMA and Hcy levels, and the presence of vascular disease, as well as the potential interactions between serum ADMA levels and seizure control.

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men

We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different ethnicity are required to confirm our findings.

Homocysteine and holotranscobalamin and the risk of Alzheimer disease

To examine the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident Alzheimer disease (AD) in a sample of Finnish community-dwelling elderly. A dementia-free sample of 271 subjects aged 65-79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. The odds ratios (ORs) (95% confidence interval [CI]) for AD were 1.16 (1.04-1.31) per increase of 1 μmol/L of tHcy at baseline and 0.980 (0.965-0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE ε4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95% CI) for AD became 1.19 (1.01-1.39) for tHcy and 0.977 (0.958-0.997) for holoTC. Adjusting for holoTC attenuated the tHcy-AD link (OR changed from 1.16 to 1.10, 95% CI 0.96-1.25). The holoTC-AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95% CI 0.968-1.000). Addition of folate did not change any of the results. This study suggests that both tHcy and holoTC may be involved in the development of AD. The tHcy-AD link may be partly explained by serum holoTC. The role of holoTC in AD should be further investigated.

Spotlight on the October 19 Issue

This study followed 271 dementia-free subjects aged 65–79 years for 7 years to detect incident Alzheimer disease. The association between serum total homocysteine (tHcy) and holotranscobalamin (holoTC) was assessed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. Serum tHcy and holoTC may be involved in the development of Alzheimer disease. See p. 1408 From editorialist Sudha Seshadri: “This article is an important initial step relating plasma holoTC to risk of …

Role of PERK/eIF2a signaling pathway in hepatocyte apoptosis of alcoholic liver injury rats

To investigate the role of PERK/eIF2alpha signaling pathway in hepatocyte apoptosis of alcoholic liver injury rats. Rat models with ethanol-induced liver injury were successfully developed by gastric gavage with ethanol-corn oil mixtures for 12 weeks. At different time points (4, 6, 10, 12 week), liver pathology was dynamically observed. The hepatocyte apoptosis was quantitatively analyzed by Annexin V-FITC/PI double-labeled flow cytometry, the serum total homocysteine (tHCY) level was detected by ELISA and the expressions of eIF2a, p-eIF2a, GRP78/Bip, GRP94, caspase-3 and caspase-12 in liver were examined using Real-time PCR and Western blot. Typical acute liver injury and chronic liver injury were observed at week 4 and week 12 respectively. The hepatocyte apoptosis rates in 6-week model rats significantly increased compared with normal rats (P value less than 0.05), and the degree of hepatocyte apoptosis continued to increase with the modeling time, and the percentages of early and total apoptosis reached 26% and 29% at week 12. From week 6 to week 12, the serum tHCY levels in model rats were obviously higher than in normal rats (P value less than 0.01). Since week 4, eIF2a protein phosphorylation in model rat livers remarkably elevated compared with that in normal rat livers (P value less than 0.01), and at week 12 the peIF2a protein expression in model rat livers increased by 2.81-fold. Since week 4 the expressions of GRP78/Bip, GRP94, caspase-12 and caspase-3 mRNA and protein in model rat livers showed a significant increase as compared to normal rat livers, and at week 12, these gene and protein levels increased 4.70, 12.95, 3.83, 4.05 fold and 3.93, 6.93, 9.88, 3.31 fold, respectively (P value less than 0.01). Activation of PERK/eIF2a signaling pathway contributes to the occurrence and development of hepatocyte apoptosis in alcoholic liver injury rats and it might be as a potential target for therapeutic applications in alcoholic liver diseases.

Serum Folate, Vitamin B-12, and Homocysteine and Their Association With Depressive Symptoms Among U.S. Adults

To examine, in a nationally representative sample of U.S. adults, the associations of serum folate, vitamin B-12, and total homocysteine (tHcy) levels with depressive symptoms. Several nutritional and physiological factors have been linked to depression in adults, including low folate and vitamin B-12 and elevated tHcy levels. Data on U.S. adults (age, 20-85 years; n = 2524) from the National Health and Nutrition Examination Survey during the period 2005 to 2006 were used. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ), and elevated symptoms were defined as a PHQ total score of ≥10. Serum folate, vitamin B-12, and tHcy were mainly expressed as tertiles. Multiple ordinary least square (OLS), logistic, and zero-inflated Poisson regression models were conducted in the main analysis. Overall, mean PHQ score was significantly higher among women compared with men. Elevated depressive symptoms (PHQ score of ≥10) were inversely associated with folate status, particularly among women (fully adjusted odds ratio [tertiles T(3) versus T(1)] = 0.37; 95% confidence interval, 0.17-0.86), but not significantly related to tHcy or vitamin B-12. No interaction was noted between the three exposures in affecting depressive symptoms. In older adults (≥50 years) and both sexes combined, tHcy was positively associated with elevated depressive symptoms (fully adjusted odds ratio [tertiles T(2) versus T(1)] = 3.01; 95% confidence interval, 1.01-9.03), although no significant dose-response relationship was found. Future interventions to improve mental health outcomes among U.S. adults should take into account dietary and other factors that would increase levels of serum folate.

Polymorphism of MTHFR C677T, serum vitamin levels and cognition in subjects with hyperhomocysteinemia in China

Relationships between hyperhomocysteinemia (HHE) and neurodegenerative diseases have been widely studied. However, the impact of serum total homocysteine (tHcy) levels on cognitive function has not been confirmed. C677T polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have impacts on tHcy level; it is suspected to influence cognitive function, but only few investigations have assessed its effects on non-dementia adults and the results have been controversial. Moreover, there is no report about Chinese subjects. In the present study, we determined C677T/MTHFR genotype, serum tHcy concentration and cognition in 182 nondemented subjects aged 55–88 years to probe the associations between MTHFRC677T mutation, increased tHcy levels and decreased cognitive function in a northern city in China. A serum tHcy level ≥ 16 μmol/l was deemed HHE. Cognitive function was assessed by the Mini Mental State Examination (MMSE) and Basic Cognitive Aptitude Tests (BCAT). Results showed that: (i) subjects with the T allele had higher serum tHcy levels than those without, especially in lower folate status; (ii) T allele and CT/TT genotype frequencies in subjects with HHE were higher than in non-HHE subjects (P < 0.05); and (iii) serum tHcy level was inversely related to total BCAT score (P < 0.05) but MTHFR677 C to T polymorphism had no association with it. Our results confirmed that the MTHFR 677 C to T mutation, especially in lower serum folate concentration status, results in the increase of serum tHcy levels which is bad for cognitive function and indicates that higher serum folate level is of benefit in keeping lower serum tHcy level and better cognitive function. The results provide some valuable clues for individualized nutrition intervention of HHE and cognition decline in the middle-aged and the elderly.