Methylenetetrahydrofolate Reductase Gene C677T and A1298C Polymorphisms, Plasma Homocysteine, Folate, and Vitamin B 12 Levels and the Extent of Coronary Artery Disease Klaus Ko ¨lling, MD, Gjin Ndrepepa, MD, Werner Koch, PhD, Siegmund Braun, MD, Julinda Mehilli, MD, Albert Scho ¨mig, MD, and Adnan Kastrati, MD The question of whether mild hyperhomocysteinemia is a risk factor for coronary artery disease (CAD) has long been debated and is still unclear. We investigated whether there is a link between methylenetetrahydrofo- late reductase (MTHFR) gene C677T and A1298C poly- morphisms or plasma homocysteine and CAD. This is a case-control study that included 2,121 consecutive pa- tients (cases) with angiographically proved CAD and 617 patients without CAD (controls). MTHFR gene C677T and A1298C polymorphisms, plasma homocysteine, fo- late, and vitamin B 12 concentrations were determined and coronary angiography was performed in all sub- jects. The distribution of MTHFR gene C677T genotypes in patients (or controls) was: CC-genotype in 915 cases, 43.1% (266 controls, 43.1%); CT-genotype in 955 cases, 45.0%, (283 controls, 45.9%); and TT-genotype in 251 cases, 11.9% (68 controls, 11.0%) (p  0.84). The dis- tribution of MTHFR gene A1298C genotypes in patients (or controls) was: AA-genotype in 973 cases, 45.9% (281 controls, 45.5%); AC-genotype in 905 cases, 42.7% (284 controls, 46.0%); and CC-genotype in 243 cases, 11.4% (52 controls, 8.5%) (p  0.07). Patients with CAD had higher levels of plasma homocysteine (12.9  5.1 vs 11.9  4.5 mol/L, p <0.001) and lower levels of folate (9.5  3.1 vs 9.9  3.8 ng/ml, p  0.008) than controls. After adjustment for other risk factors for CAD, plasma homocysteine (p  0.89), MTHFR gene C677T (p  0.38), or A1298C polymor- phisms (p  0.13) were not independent correlates of CAD. This study demonstrated that MTHFR gene C677T or A1298C polymorphisms are not associated with the presence of angiographic CAD. Although there is an apparent association between elevated levels of homo- cysteine and CAD, this association is not independent of conventional cardiovascular risk factors. 2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1201–1206) M ultiple factors and conditions lead to mild in- creases in the plasma concentrations of homo- cysteine. 1–4 It is well established that genetic poly- morphisms of the genes that encode enzymes involved in the homocysteine metabolism, particularly methyl- enetetrahydrofolate reductase (MTHFR), are a com- mon cause of mild increases in the levels of circulat- ing homocysteine. 1 MTHFR gene C677T and A1298C polymorphisms are common. The C677T polymor- phism in the MTHFR gene is associated with reduced enzyme activity 5 and increased levels of plasma ho- mocycteine of about 25%. 1 In contrast, it appears that the A1298C polymorphism alone does not signifi- cantly affect plasma homocysteine but may do so when combined with the 677T variant (AC/CT com- bination). 6 The relation between the MTHFR C677T and A1298C gene polymorphisms and coronary artery disease (CAD) risk has not been clearly established. Contradictory results have also been reported concern- ing the rate of atherosclerosis and cardiovascular risk in carriers of the TT-genotype of the MTHFR gene. 1,7 Furthermore, a causal link between mild hyperhomo- cysteinemia and CAD has never been proved beyond reasonable doubt and continues to be a subject of debate. We undertook this study to investigate whether there is a link between MTHFR gene C677T and A1298C poly- morphisms or plasma homocysteine levels and the presence and extent of CAD in a large series of patients who underwent coronary angiography. METHODS Study population: This is a case-control study. The diagnosis of CAD was confirmed or excluded by coronary angiography. The group of cases was formed by a consecutive series of 2,121 Caucasian patients with angiographically significant CAD (coronary ste- noses of 50% lumen obstruction in 1 of the 3 major coronary arteries). The group of controls in- cluded 617 consecutive Caucasian patients with nor- mal coronary angiograms (with arterial vessel irregu- larities of 10% lumenal narrowing, at most) and without regional left ventricular wall motion abnor- malities. All participants in the study gave written From Deutsches Herzzentrum and 1. Medizinische Klinik rechts der Isar der Technischen, Universita ¨t Munich, Munich, Germany. Manuscript received November 6, 2003; revised manuscript received and ac- cepted January 30, 2004. Address for reprints: Gjin Ndrepepa, MD, Deutsches Herzzen- trum, Lazarettstrasse 36, 80636 Mu ¨nchen, Germany. E-mail: ndrepepa@dhm.mhn.de. 1201 ©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matter The American Journal of Cardiology Vol. 93 May 15, 2004 doi:10.1016/j.amjcard.2004.02.009