Homocysteine and Risk of Ischemic Heart Disease and Stroke

Clarke, Robert; Collins, Rory; Lewington, Sarah; Donald, Alan; Alfthan, Georg; Tuomilehto, Jaakko; Arnesen, Egil; Bønaa, Kaare Harald; Blacher, Jacques; Boers, G.H.J.; Bostom, Andrew G.; Bots, Michiel L.; Grobbee, Diederick E.; Brattström, Lars; Breteler, Monique M.B.; Hofman, Albert; Chambers, John C.; Kooner, Jaspal S.; Coull, Bruce M.; Evans, Rhobert W.; Kuller, Lewis H.; Evers, Stefan; Folsom, Aaron R.; Freyburger, G.; Parrot, F; Genest, Jacques; Dalery, Karl; Graham, Ian; Daly, Leslie; Hoogeveen, Ellen K.; Kostense, Pieter J.; Stehouwer, Coen D.A.; Hopkins, P N; Jacques, Paul F.; Selhub, Jacob; Luft, Friedrich C.; Jungers, Paul; Lindgren, Arne; Lolin, Y. I.; Loehrer, F.; Fowler, Brian; Mansoor, M. A.; Malinow, M. R.; Ducimetière, Pierre; Nygård, Ottar; Refsum, Helga; Vollset, Stein Emil; Ueland, Per Magne; Omenn, Gilbert S.; Beresford, Shirley A.A.; Roseman, Jeffrey M.; Parving, Hans‐Henrik; Gall, Mari-Anne; Perry, Ivan J.; Ebrahim, Shah; Shaper, A. G.; Robinson, Killian; Jacobsen, Donald W.; Schwartz, Steven M.; Siscovick, David S.; Stampfer, Meir J.; Hennekens, Charles H.; Feskens, Edith J. M.; Kromhout, Daan; Ubbink, Johan B.; Elwood, Peter Creighton; Pickering, Janet Elizabeth; Verhoef, Petra; Eckardstein, Arnold von; Schulte, Helmut; Assmann, Gerd; Wald, Nicholas; Law, Malcolm; Whincup, Peter H; Wilcken, D. E. L.; Sherliker, Paul; Linksted, Pamela; Smith, G. Davey

doi:10.1001/jama.288.16.2015

Cited by 1,830 publications

(324 citation statements)

References 60 publications

Supporting

Mentioning

312

Contrasting

Unclassified

Order By: Relevance

“…This magnitude of tHcy-lowering effect is consistent with the projected average treatment effect of a 4.0 µmol/l reduction with folic acid-based multivitamin therapy that has been previously demonstrated [9], and should ensure adequate statistical power to reliably identify an expected reduction in risk of the composite outcome of stroke, myocardial infarction and vascular death of at least 15% [7, 10, 11]. However, this also requires that a similar magnitude of treatment effect is maintained throughout the duration of the trial, despite increasing voluntary folic acid fortification of food in Australia and other countries in which the VITATOPS trial is being conducted.…”

Section: Introductionsupporting

confidence: 81%

“…A recent systematic review of individual patient data from 30 prospective and retrospective studies involving a total of 5,073 coronary events and 1,113 stroke events indicated that, after adjusting for confounding caused by known vascular risk factors and correction for regression dilution caused by random variation in homocysteine measurements, a 25% lower usual tHcy concentration in the blood [about 3 µmol/l (0.41 mg/l)] was associated with an 11% (OR 0.89, 95% CI 0.83–0.96) lower risk of a coronary event, and a 19% (OR 0.81, 95% CI 0.69–0.95) lower stroke risk [10]. Concurrently, another recent systematic review of 20 prospective studies (involving 3,820 participants) of serum homocysteine and disease risk concluded that lowering homocysteine concentrations by 3 µmol/l from current levels (achievable by increasing daily intake of about 0.8 mg folic acid) would reduce the risk of stroke by 24% (95% CI 15–33%) and ischemic heart disease by 16% (11–20%) [11].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sustained Homocysteine-Lowering Effect over Time of Folic Acid-Based Multivitamin Therapy in Stroke Patients despite Increasing Folate Status in the Population

Hankey¹,

Eikelboom²,

Loh³

et al. 2005

Cerebrovasc Dis

View full text Add to dashboard Cite

Background and Aims: It is uncertain what impact increasing voluntary folate fortification may be having on the statistical power of randomized trials testing the homocysteine hypothesis of atherothrombosis. The objective of this study was to determine whether there has been a change in folate status between 1998 and 2002 in stroke patients randomized into the VITAmins TO Prevent Stroke (VITATOPS) Study at a single center in Perth, Australia, and what impact this may have had on the magnitude of the homocysteine-lowering effect achieved over time with folic acid-based multivitamin therapy. Methods: We conducted a randomized, double-blind, placebo-controlled study involving 285 patients with stroke or transient ischemic attack who were recruited between 1998 and 2002 and randomized to long-term folic acid 2.0 mg/day, pyridoxine 25 mg/day and cobalamin 0.5 mg/day (active VITATOPS medication) or placebo. Fasting plasma total homocysteine, red cell folate, serum cobalamin and serum pyridoxine levels were measured at baseline and 6 months, and the change in blood levels over 4 time quartiles and differences in levels between the two randomized treatments were examined. Results: Between 1998 and 2002, there was a significant rise in baseline mean red cell folate levels over 4 time quartiles among the entire stroke cohort (723.3, 780.1, 922.6 and 1,023.7 nmol/l in the first, second, third and fourth quartiles, respectively; p < 0.0001), but this was not associated with a spontaneous reduction in mean baseline total homocysteine levels during the same time period (12.7, 14.3, 12.1 and 12.8 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.55). The homocysteine-lowering effect of the active VITATOPS trial medication at 6 months after randomization also did not change significantly between 1998 and 2002 (difference between randomized groups: –4.1, –4.1, –3.1 and –3.6 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.56). Conclusions: The homocysteine-lowering effect of the active VITATOPS trial medication has not attenuated significantly in the past 5 years despite increasing voluntary fortification of foods with folic acid as reflected by a progressive rise in baseline folate status. These data suggest that in the continuing absence of a program of mandatory folate fortification of food in populations served by centers participating in the VITATOPS trial, the study will remain adequately powered to test the homocysteine-lowering hypothesis for which it was designed.

show abstract

Section: Introductionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Sustained Homocysteine-Lowering Effect over Time of Folic Acid-Based Multivitamin Therapy in Stroke Patients despite Increasing Folate Status in the Population

Hankey¹,

Eikelboom²,

Loh³

et al. 2005

Cerebrovasc Dis

View full text Add to dashboard Cite

show abstract

“…Inadequate folate intake constitutes a leading cause of folate deficiency, which involves decreased serum or plasma folate concentrations followed by increased serum or plasma total homocysteine (tHcy) concentrations and reduced red blood cell (RBC) folate levels. Elevated tHcy represents a major risk factor of cardiovascular and cerebrovascular diseases (Homocysteine Studies Collaboration 2002). Moreover, lower serum folate and higher plasma tHcy may also be causes of neural tube defects (NTDs) (Smithells et al 1976; Daly et al 1995), cognitive dysfunction (Seshadri et al 2002), and depression (Bottiglieri 2005).…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms and folate status

Hiraoka

Kagawa

2017

Congenital Anomalies

134

102

View full text Add to dashboard Cite

Moderate hyperhomocysteinemia‐induced low folate status is an independent risk factor for cardiovascular disease, dementia, and depression. Folate is an essential cofactor in the one‐carbon metabolism pathway and is necessary in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. In the folate cycle and homocysteine metabolism, folate, vitamin B12, vitamin B6, and vitamin B2 are important cofactors. Many enzymes are involved in folate transport and uptake, the folate pathway, and homocysteine (Hcy) metabolism, and various polymorphisms have been documented in these enzymes. Serum folate and total Hcy (tHcy) levels are influenced by folate intake and genetic polymorphisms in 5,10‐methylenetertahydrofolate reductase (MTHFR) such as C677T. The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, with a frequency of approximately 15% in Japanese populations. Individuals with the TT genotype have significantly higher tHcy levels and lower folate levels in serum than those with the CT and TT genotypes. However, administration of folic acid has been shown to eliminate these differences. Moreover, data have suggested that interventions based on genotype may be effective for motivating individuals to change their lifestyle and improve their nutrition status. Accordingly, in this review, we discuss the effects of MTHFR C677T polymorphisms on serum tHcy and folate levels with folic acid intervention and evaluate approaches for overcoming folic acid deficiency and related symptoms.

show abstract

“…On the other hand, there are studies showing an increased risk of arterial thrombotic complication in patients with VTE (7). The role of inherited thrombophilia in ATE is less clear but hyperhomocysteinemia, inherited or acquired, has been demonstrated to be an independent risk factor for atherothrombosis (8). Two polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene -C677T and A1298C -are the most common inherited causes of hyperhomocysteinemia.…”

Section: Thrombophilia Genetic Testing In Romanian Young Womenintrodumentioning

confidence: 99%