Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotypes, and Age at Onset of Symptoms of Myocardial Ischemia Aviv Mager, MD, Alexander Battler, MD, Yochai Birnbaum, MD, Nurit Magal, PhD, and Mordechai Shohat, MD Elevated fasting plasma homocysteine is a graded risk factor of coronary artery disease (CAD) and may accel- erate onset of CAD. Homozygosity for the C677T muta- tion in the methylenetetrahydrofolate reductase (MTHFR) gene is commonly but inconsistently associated with hyperhomocysteinemia. In the present study we exam- ined the possible relation between levels of fasting plasma homocysteine and age at CAD onset in different MTHFR genotypes. We studied 182 patients with CAD, 74 patients with early onset CAD (aged <45 years), and 108 patients with later onset CAD (aged 46 to 65 years). Plasma homocysteine levels in 90 subjects without CAD were used for control. Fasting plasma homocysteine levels in T/T homozygotes with early onset CAD (20.2 12.5 mol/L) was markedly higher than in T/T ho- mozygotes with later onset CAD (13.4  6.8 mol/L) and in patients with early onset CAD who were not T/T homozygotes (11.9  3.7 mol/L; p  0.034 and p  0.0001, respectively). CAD developed earlier in T/T ho- mozygotes who were hyperhomocysteinemic (>15 mol/L) than in the T/T homozygotes who were not (p  0.036). Plasma homocysteine levels had no effect on age at onset of CAD in patients who were non-T/T genotypes. Homocysteine levels in control subjects and in patients who were non-T/T genotypes were compa- rable and were not influenced by age. The results reveal an inverse relation between the level of fasting plasma homocysteine and age at onset of CAD in T/T homozy- gotes as opposed to no association in patients who were non-T/T genotypes. Additionally, these results show that hyperhomocysteinemia and the T/T genotype have a stronger effect on the pathogenesis of CAD when they are combined, and that a marked increase (>15 mol/L) in fasting plasma homocysteine in T/T homozy- gotes is a risk factor for early onset of CAD. 2002 by Excerpta Medica, Inc. (Am J Cardiol 2002;89:919 –923) F asting plasma homocysteine is a graded and inde- pendent risk factor for coronary 1–3 and other forms of vascular disease, 4,5 as well as a strong predictor of mortality. 6 Some investigators 7,8 have found an asso- ciation between plasma homocysteine and early onset of coronary artery disease (CAD), but this was not confirmed by others. 9 Methylenetetrahydrofolate re- ductase (MTHFR) is a key enzyme in homocysteine metabolism. MTHFR deficiency results in homocys- teinuria, 10 a rare genetic disorder characterized by development of CAD very early in life. A common point mutation (C677T) in the MTHFR gene renders this enzyme thermolabile and less active. 11 Ho- mozygosity for this mutation is typically but inconsis- tently associated with hyperhomocysteinemia 11–15 and with CAD. 12–20 Interestingly, studies that re- ported an association between the C677T mutation and CAD often included younger patients. 17,19,21 In the present study we examined the possible associa- tion between levels of fasting plasma homocysteine and age at onset of CAD in patients with CAD with different MTHFR genotypes. METHODS The study candidates consisted of 210 consecutive patients with CAD from our Coronary Clinic. Inclu- sion criteria were onset of CAD symptoms at 65 years of age and angiographically documented CAD (50% stenosis of 1 epicardial coronary artery) or well-documented myocardial infarction diagnosed by clinical, electrocardiographic, and enzymatic criteria. All the patients underwent coronary angiography for purposes unrelated to this study. Patients with renal failure (serum creatinine 1.4 mg/dl), severe systemic disease, hypothyroidism, and known vitamin B12 de- ficiency, and patients taking medications or vitamins that could affect plasma homocysteine levels, were excluded. Ten additional patients were referred from other clinics. Of the original group, 2 died, 1 devel- oped renal failure, and 35 could not be contacted or were not willing to participate. The final study popu- lation consisted of 182 patients. All were interviewed to collect data on smoking habits, body height and weight, use of medications including vitamins, age at onset of CAD symptoms, previous myocardial infarc- tion, hypertension (blood pressure 140/90 mm Hg or From the Departments of Cardiology and Medical Genetics, Rabin Medical Center-Beilinson Campus and Felsenstein Medical Research Center, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv Uni- versity, Tel Aviv, Israel. Manuscript received August 29, 2001; revised manuscript received and accepted December 27, 2001. Address for reprints: Aviv Mager, MD, Department of Cardiology, Rabin Medical Center-Beilinson Campus, Petah Tiqva 49100, Israel. E-mail: mager@netvision.net.il. 919 ©2002 by Excerpta Medica, Inc. All rights reserved. 0002-9149/02/$–see front matter The American Journal of Cardiology Vol. 89 April 15, 2002 PII S0002-9149(02)02239-7