Current issues of ACP Journal Club are published in Annals of Internal Medicine


High homocysteine levels were associated with increased CHD in men

ACP J Club. 1998 Sep-Oct;129:51. doi:10.7326/ACPJC-1998-129-2-051

Source Citation

Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischemic heart disease. Results of prospective study with implications regarding prevention. Arch Intern Med. 1998 Apr 27;158:862-7.



Are homocysteine levels associated with coronary heart disease (CHD) in men?


Nested case-control study of men in the British United Provident Association study with mean follow-up of 8.7 years.


London, England, United Kingdom.


21 520 men aged 35 to 64 years were enrolled from 1975 to 1982. Case-participants (n = 229) were men who had died from CHD before 1988 and who did not have a history of CHD at baseline. 5 control-participants per case-participant (n = 1126) were matched for age and length of storage of serum samples. These men had not died from CHD and had no history of CHD at baseline.

Assessment of risk factors

Homocysteine levels were measured using frozen serum stored at baseline. Men were divided into quartiles of homocysteine levels (< 10.25, 10.25 to 12.32, 12.33 to 15.16, and ≥ 15.17 µmol/L). Other risk factors were smoking status, blood pressure, serum lipid levels, serum apolipoprotein levels, weight, and body mass index.

Main outcome measure

Deaths from CHD were ascertained from national death registries.

Main results

Men (case-participants) who died from CHD had a mean homocysteine level of 13.1 µmol/L compared with 11.8 µmol/L for men who did not (control-participants) (P < 0.001). Odds ratios (ORs) were calculated with adjustment for apolipoprotein B levels and systolic blood pressure; the OR for the lowest quartile of homocysteine levels was set at 1.00. Men in the other 3 quartiles of homocysteine levels had an increased risk for CHD when compared with men in the lowest quartile (Table). A dose-response relation was shown with each 5-µmol/L increase in serum homocysteine levels (adjusted OR 1.33, 95% CI 1.22 to 1.59).


High homocysteine levels were associated with an increased risk for death from coronary heart disease in men.

Source of funding: BUPA Medical Foundation.

For correspondence: Dr. N.J. Wald, Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, England, UK. FAX 44-171-982-6270.

Table. Odds ratios for death from coronary heart disease for quartiles of homocysteine levels in men*

Homocysteine levels Mean homocysteine level Odds ratio (95% CI)
< 10.25 µmol/L 8.77 µmol/L 1.00 (0.73 to 1.38)
10.25 to 12.32 µmol/L 11.26 µmol/L 1.43 (1.07 to 1.92)
12.33 to 15.16 µmol/L 13.56 µmol/L 1.46 (1.08 to 1.97)
≥ 15.17 µmol/L 19.13 µmol/L 2.90 (2.04 to 4.12)

*Adjusted for apolipoprotein B levels and systolic blood pressure.


Raised homocysteine levels can be caused by several inborn errors of metabolism, and these errors have been implicated in causing CHD since 1969 (1). Slightly elevated homocysteine levels can also be caused by nutritional, physiologic, and pathologic factors. Inborn errors of metabolism are rare; mild elevations of homocysteine levels are usually caused by other factors. In vitro and animal studies show that hyperhomocysteinemia increases vascular and platelet damage, but despite good evidence from retrospective case-control studies, prospective studies have not shown a consistent association between hyperhomocysteinemia and risk for CHD.

The large prospective survey of middle-aged men by Wald and colleagues provides new evidence of a substantial risk for CHD associated with raised homocysteine levels. A clear dose-response effect was shown, but the increased risk was relatively small except in patients with the highest homocysteine levels (≥ 15.17 µmol/L). Potential bias caused by the storage of serum samples was avoided by matching case and control samples by length of storage time.

Homocysteine levels can be reduced by folic acid supplementation (2), suggesting that a diet rich in folic acid may decrease the risk for heart disease. Vitamin supplements should not be widely recommended, however, until a substantial reduction in cardiovascular disease has been shown in a randomized controlled trial. This trial should establish both the optimal dose of folic acid and whether a threshold below which homocysteine levels cannot be reduced exists. The potential benefits of therapy should be compared with the costs of treatment and screening and evaluated in light of other risk-reducing strategies for cardiovascular disease.

Gillian Leng, MBChB, MD
Royal Free Hospital School of MedicineLondon, England, UK

Gillian Leng, MBChB, MD
Royal Free Hospital School of Medicine
London, England, UK


1. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56:111-28.

2. Ward M, McNulty H, McPartlin J, et al. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM. 1997;90:519-24.