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August 2009

Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese.

BACKGROUND: To date, no prospective studies have examined the association between serum homocysteine levels and the risk of stroke and stroke subtypes in Asian populations. METHODS AND RESULTS: A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11,846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for the other two communities. By the end of 2000, we identified 150 incident strokes, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Serum total homocysteine levels were measured by high-performance liquid chromatography. Compared with control subjects, total (n=150), hemorrhagic (n=52), and ischemic (n=98) strokes had higher geometric mean values of total homocysteine and higher proportions of homocysteine > or =11.0 micromol/L. The multivariate odds ratios (95% CI) for highest (> or =11.0 micromol/L) versus lowest quartiles (<7.0 micromol/L) of homocysteine after adjustment for body mass index, smoking, alcohol intake, hypertension, serum total cholesterol, and other cardiovascular risk factors were 2.99 (1.51 to 5.93) for total stroke, 3.89 (1.60 to 9.46) for ischemic stroke, 3.36 (1.27 to 8.90) for lacunar infarction, and 1.63 (0.44 to 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5-micromol/L increase in homocysteine were 1.40 (1.09 to 1.80), 1.52 (1.07 to 2.14), 1.48 (1.01 to 2.18), and 1.10 (0.76 to 1.59). The excess risk of total and ischemic strokes did not vary significantly according to sex, age, smoking status, or hypertensive status. CONCLUSIONS: High total homocysteine concentrations were associated with the increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women.

Circulation. 2004 Jun 8;109(22):2766-72

The methylation, neurotransmitter, and antioxidant connections between folate and depression.

Depression is common - one-fourth of the US population will have a depressive episode sometime in life. Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response.

Altern Med Rev. 2008 Sep;13(3):216-26

Homocysteine levels and risk of hip fracture in postmenopausal women.

BACKGROUND: Recent studies suggest that high homocysteine levels are associated with an increased risk of fractures. Homocysteine levels are known to be influenced by vitamin B and folate supply or status, and poor renal function can result in higher levels independent of nutritional adequacy. OBJECTIVE: The aim of the study was to determine the associations between fasting homocysteine levels and incident hip fractures, and the effects of other factors on hip fracture risk. DESIGN: We conducted a case-control study in the Women’s Health Initiative Observational Study, a study of postmenopausal women (n = 93,676) recruited in the United States. We selected 400 incident cases of hip fracture and 400 controls matched on age, ethnicity, and blood draw date among women not on osteoporosis therapies. Outcome measures included physician-adjudicated, incident hip fractures. Baseline lifestyle and nutritional questionnaires were performed. RESULTS: The risk of hip fracture increased 1.38-fold [95% confidence interval (CI), 1.14, 1.66] for each sd increase in serum homocysteine level after adjustment for fracture risk factors. This association was not affected by adjustment for dietary folate, B6, or B12 intake, but it diminished after adjustment for cystatin-C level (odds ratio, 1.08; 95% CI, 0.66-1.79), a measure of renal function not affected by muscle mass. Among women in the highest quartile of homocysteine and cystatin-C compared to those without elevations in either biomarker, the risk of hip fracture was substantially elevated (odds ratio, 2.8; 95% CI, 1.61-4.87). CONCLUSIONS: This study indicates that high homocysteine levels are associated with an increased risk of hip fracture, which could be accounted for by poor renal function.

J Clin Endocrinol Metab. 2009 Apr;94(4):1207-13

B vitamins, homocysteine, and bone disease: epidemiology and pathophysiology.

Observational studies indicate that mildly elevated homocysteine is a strong risk factor for osteoporotic fracture, yet there is no clear biologic mechanism for an effect of homocysteine on bone. The association could instead be attributed to B vitamins (folate, vitamin B(12), vitamin B(6)), as low levels of these nutrients are the primary determinants of homocysteine and may be associated with lower bone quality. Discovery of a direct effect of homocysteine or B vitamins on bone would be important in terms of interventions, as these factors can be modified with changes in diet or supplementation. This article reviews the connections of homocysteine and B vitamins to measures of bone quality and osteoporotic fracture. Although the literature suggests that these factors may be associated with bone health, most of the epidemiologic studies are observational, limiting conclusions regarding causality. More controlled trials are needed to determine whether treatment with B vitamins would reduce fracture rates among community-dwelling cohorts.

Curr Osteoporos Rep. 2007 Sep;5(3):112-9

Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study.

PURPOSE: To assess associations between increased serum homocysteine, low vitamin B12, low folate, and age-related macular degeneration (AMD). DESIGN: Population-based, cross-sectional analysis. METHODS: Serum homocysteine, vitamin B12, and folate were measured in 2,335 participants of the Blue Mountains Eye Study second survey. AMD detected from retinal photographs included atrophic or neovascular lesions. RESULTS: After adjusting for age, gender, and smoking in logistic regression models, homocysteine >15 micromol/l was associated with an increased likelihood of AMD in participants aged <75 years (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.09 to 9.43). A similar association was found for vitamin B12 <125 pmol/l (OR 2.30, 95% CI 1.08 to 4.89) among all participants. In participants with homocysteine < or =15 micromol/l, low serum B12 was associated with nearly four-fold higher odds of AMD (OR 3.74, 95% CI 1.06 to 13.24). Folate was not statistically significantly associated with AMD. CONCLUSIONS: Increased homocysteine and low vitamin B12 were independently associated with an increased risk of AMD in this study population.

Am J Ophthalmol. 2007 Feb;143(2):344-6

Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women’s Antioxidant and Folic Acid Cardiovascular Study.

BACKGROUND: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 5,442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5,205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition. RESULTS: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]). CONCLUSIONS: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.

Arch Intern Med. 2009 Feb 23;169(4):335-41

Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.

CONTEXT: It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke. OBJECTIVE: To assess the relationship of homocysteine concentrations with vascular disease risk. DATA SOURCES: MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators. STUDY SELECTION: Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete. DATA EXTRACTION: Data from 30 prospective or retrospective studies involving a total of 5,073 IHD events and 1,113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression. DATA SYNTHESIS: Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk. CONCLUSIONS: This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.

JAMA. 2002 Oct 23-30;288(16):2015-22

In pregnant women who smoke, caffeine consumption is associated with an increased level of homocysteine.

AIM. To investigate whether maternal caffeine consumption is associated with increased maternal homocysteine (Hcy) levels in uncomplicated pregnancies. METHODS. Ninety-two pregnant women were randomly selected, and maternal serum levels of folate, vitamin B(12), and Hcy at gestational weeks 17 and 33 were measured. Caffeine consumption was estimated from dietary records collected at the same gestational ages. RESULTS. In women who smoked, Hcy levels were associated with caffeine consumption both in gestational weeks 17 and 33 and with folate at week 33. Consumption of one cup of coffee was associated with an increase in maternal Hcy of 0.26 micromol/l at week 17 and 0.69 micromol/l at week 33, indicating that one extra cup (150 ml) of coffee per day may increase Hcy by 5--10% in pregnant smokers. In non-smokers, caffeine consumption was not associated with Hcy levels. CONCLUSIONS. In uncomplicated pregnancies, maternal caffeine consumption early in the second and in the third trimester is associated with increased maternal Hcy levels in women who smoked, but not in non-smokers.

Acta Obstet Gynecol Scand. 2005 Nov;84(11):1049-54

Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study.

OBJECTIVE—To estimate the relations between established cardiovascular risk factors and total homocysteine (tHcy) in plasma. DESIGN—Health examination survey by the Norwegian Health Screening Service in 1992 and 1993. SETTING—General community, Hordaland County of Western Norway. PARTICIPANTS—A total of 7,591 men and 8,585 women, 40 to 67 years of age, with no history of hypertension, diabetes, coronary heart disease, or cerebrovascular disease were included. MAIN OUTCOME MEASURE—Plasma tHcy level. RESULTS—The level of plasma tHcy was higher in men than in women and increased with age. In subjects 40 to 42 years old, geometric means were 10.8 mumol/L for 5918 men and 9.1 mumol/L for 6,348 women. At age 65 to 67 years, the corresponding tHcy values were 12.3 mumol/L (1,386 men) and 11.0 mumol/L (1,932 women). Plasma tHcy level increased markedly with the daily number of cigarettes smoked in all age groups. Its relation to smoking was particularly strong in women. The combined effect of age, sex, and smoking was striking. Heavy-smoking men aged 65 to 67 years had a mean tHcy level 4.8 mumol/L higher than never-smoking women aged 40 to 42 years. Plasma tHcy level also was positively related to total cholesterol level, blood pressure, and heart rate and inversely related to physical activity. The relations were not substantially changed by multivariate adjustment, including intake of vitamin supplements, fruits, and vegetables. CONCLUSIONS—Elevated plasma tHcy level was associated with major components of the cardiovascular risk profile, ie, male sex, old age, smoking, high blood pressure, elevated cholesterol level, and lack of exercise. These findings should influence future studies on the etiology and pathogenesis of cardiovascular disease.

JAMA. 1995 Nov 15;274(19):1526-33

Homocysteine, B-vitamins and CVD.

There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14-21%) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B12 and B6. Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10% of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored.

Proc Nutr Soc. 2008 May;67(2):232-7