Association of Low Red Blood Cell Folate Concentrations with Coronary Artery Disease in Iranians: A Matched Case-Control Study

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Abstract

Background: It is not fully established whether the increasing risk of coronary artery disease (CAD) is associated with high plasma homocysteine levels or components of the homocysteine remethylation pathway, e.g. vitamin B12 or 5-methyltetrahydrofolate (5-MTHF) in plasma and red blood cells (RBC). In this study, we tested the hypothesis that 5-MTHF in RBC, which represents the long-term folate status of individuals, may be a more reliable marker of homocysteine remethylation pathway disturbances, and its deficiency may be associated with CAD in Iranians. Methods: Plasma total homocysteine (tHcy), vitamin B12, and plasma and RBC 5-MTHF were measured in 200 angiographically documented patients and 200 controls matched for sex and age. Results: In the plasma, tHcy levels were significantly higher in cases compared to controls (geometric mean 12.9 ± 6.5 vs. 10.6 ± 5.6 µmol/l, p = 0.04). However, RBC 5-MTHF (527.2 ± 185.9 vs. 461.3 ± 117.9 nmol/l, p = 0.007) and vitamin B12 (254.2 ± 132.8 vs. 182.2 ± 110.4 pmol/l, p = 0.04) were significantly higher in controls than patients. RBC 5-MTHF was a strong and independent predictor of plasma tHcy (β = –0.01, p = 0.003, r2 = 0.19). Subjects in the lowest quartile of red-cell 5-MTHF had a 2.5-fold increased prevalence of CAD compared to subjects in the highest quartile. The association of CAD in the first quartile with red-cell 5-MTHF remained significant when adjusted for plasma tHcy, vitamin B12, hypertension and hypercholesterolemia (odds ratio, OR 2.3, confidence interval: 1.1–3.9, p = 0.01). However, the association between CAD in the highest quartile and plasma tHcy decreased and became insignificant when adjusted for red-cell 5-MTHF, vitamin B12, hypertension and hypercholesterolemia (OR 1.27, confidence interval: 0.96–1.69, p = 0.11). Conclusion: In this study, the association between CAD and low RBC 5-MTHF was stronger than with plasma 5-MTHF and plasma tHcy levels, indicating that RBC 5-MTHF may be a more stable parameter to study disturbances in the homocysteine remethylation pathway in Iranians.

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Most cited references 14

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Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

D. Wald (2002)

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Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering.

Ian McDowell, Simon J. Durrant, Amanda Payne … (2002)

Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven. The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. This reduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial. It has been proposed that improvement occurs through reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy). We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD. A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment. Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; P<0.001). FMD improved at 2 hours (83 compared with 47 microm; P<0.001) and was largely complete by 4 hours (101 compared with 51 microm; P<0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 micromol/L; P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 micromol/L; P=0.02). FMD improvement did not correlate with reductions in either fHcy or tHcy at any time. These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.

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Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian Asian and European men.

John Chambers, Omar Obeid, Helga Refsum … (2000)

Reasons for the increase in mortality due to coronary heart disease (CHD) in UK Indian Asians are not well understood. In this study, we tested the hypotheses that elevated plasma homocysteine concentrations are a risk factor for CHD in Indian Asians, and explain part of their increased CHD risk, compared with Europeans. We undertook two parallel case-control studies, one in Europeans and one in Indian Asians. We recruited 551 male cases (294 European, 257 Indian Asian) and 1025 healthy male controls (507 European, 518 Indian Asian). Fasting and post-methionine load homocysteine, vitamin B12 and folate concentrations, and conventional CHD risk factors were measured. Fasting homocysteine concentrations were 8% higher (95% CI 3-14) in cases compared with controls, in both ethnic groups. The odds ratio of CHD for a 5 micromol/L increment in fasting plasma homocysteine was 1.3 (1.1-1.6) in Europeans and 1.2 (1.0-1.4) in Indian Asians. The association between fasting plasma homocysteine and CHD was independent of conventional CHD risk factors in both ethnic groups. Post-load homocysteine concentrations were not significantly different in cases compared with controls. Among the controls, fasting homocysteine concentrations were 6% (2-10) higher in Indian Asians than in Europeans. From the results we estimate that elevated homocysteine may contribute to twice as many CHD deaths in Indian Asians, compared with Europeans. The differences in homocysteine concentrations between the two ethnic groups were explained by lower vitamin B12 and folate levels in Asians. Plasma homocysteine is a novel and independent risk factor for CHD in Indian Asians, and may contribute to their increased CHD risk. Raised homocysteine concentrations in Indian Asians may be related to their reduced vitamin B12 and folate levels, implying that the increased CHD risk in this group may be reduced by dietary vitamin supplementation.

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Author and article information

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2005

Publication date (Print): August 2005

Publication date (Electronic): 29 July 2005

Volume: 42

Issue: 4

Pages: 325-330

Affiliations

^aDepartment of Biochemistry, Faculty of Medicine, and ^bDepartment of Internal Medicine, Cardiovascular Unit, Shiraz University of Medical Sciences, Shiraz, Iran

Article

Publisher ID: 86460 Other ID: J Vasc Res 2005;42:325–330

DOI: 10.1159/000086460

PubMed ID: 15970643

SO-VID: c2b5be01-8c8e-409b-9efd-331c49846e09

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