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(Circulation. 2009;119:2507-2515.)
© 2009 American Heart Association, Inc.

Vascular Medicine

MTHFR 677 C>T Polymorphism Reveals Functional Importance for 5-Methyltetrahydrofolate, Not Homocysteine, in Regulation of Vascular Redox State and Endothelial Function in Human Atherosclerosis

Charalambos Antoniades, MD, PhD; Cheerag Shirodaria, MRCP; Paul Leeson, MD, PhD, MRCP; Otto A. Baarholm, BA; Tim Van-Assche, PhD; Colin Cunnington, MD; Ravi Pillai, MD, MRCS; Chandi Ratnatunga, MD, MRCS; Dimitris Tousoulis, MD, PhD; Christodoulos Stefanadis, MD, PhD; Helga Refsum, MD, PhD; Keith M. Channon, MD, FRCP

From the Departments of Cardiovascular Medicine (C.A., C. Shirodaria, P.L., T.V.-A., C.C., R.P., C.R., K.M.C.) and Physiology, Anatomy, and Genetics (H.R.), University of Oxford, Oxford, UK; Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (O.A.B., H.R.); and Department of Cardiology, Athens University Medical School, Athens, Greece (C.A., D.T., C. Stefanadis).

Correspondence to Professor Keith M. Channon, MD, FRCP, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail keith.channon{at}cardiov.ox.ac.uk

Received July 31, 2008; accepted March 9, 2009.

Background— The role of circulating homocysteine as an atherosclerosis risk factor has recently been questioned. However, 5-methyl-tetrahydrofolate (5-MTHF), the circulating metabolite of folic acid participating in homocysteine metabolism, has direct effects on vascular function. We sought to distinguish the effects of plasma versus vascular tissue 5-MTHF and homocysteine on vascular redox and endothelial nitric oxide bioavailability in human vessels.

Methods and Results— We used the methyl tetrahydrofolate reductase (MTHFR) gene polymorphism 677C>T as a model of chronic exposure of the vascular wall to varying 5-MTHF levels in 218 patients undergoing coronary artery bypass graft surgery. Vascular superoxide, vascular 5-MTHF, and total homocysteine were determined in saphenous veins and internal mammary arteries obtained during surgery. Nitric oxide bioavailability was evaluated by organ bath studies on saphenous vein rings. MTHFR genotype was a determinant of vascular 5-MTHF (not vascular homocysteine). Both MTHFR genotype and vascular 5-MTHF were associated with vascular nitric oxide bioavailability and superoxide generated by uncoupled endothelial nitric oxide synthase. In contrast, vascular homocysteine was associated only with NADPH-stimulated superoxide.

Conclusions— Genetic polymorphism 677 C>T on MTHFR affects vascular 5-MTHF (but not homocysteine) and can be used as a model to distinguish the chronic effects of vascular 5-MTHF from homocysteine on vascular wall. Vascular 5-MTHF, rather than plasma or vascular homocysteine, is a key regulator of endothelial nitric oxide synthase coupling and nitric oxide bioavailability in human vessels, suggesting that plasma homocysteine is an indirect marker of 5-MTHF rather than a primary regulator of endothelial function.

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