A comprehensive study in this week's PLoS Medicine shows levels of the amino acid, homocysteine, have no meaningful effect on the risk of developing coronary heart disease, closing the door on the previously suggested benefits of lowering homocysteine with folate acid once and for all.
Previous studies have suggested that high blood levels of homocysteine might be a modifiable risk factor for coronary heart disease, but in a detailed analysis of data from 19 unpublished and 86 published studies, led by Robert Clarke from the Clinical Trial Service Unit and Epidemiological Studies Unit at the University of Oxford, the researchers found that lifelong moderate elevation of homocysteine levels had no significant effect on the risk of developing coronary heart disease. The study findings suggest that extensive publication bias, together with methodological problems, has played a role in previous suggestions linking homocysteine with coronary heart disease risk.
In their analysis, the authors found that in almost 50 000 individuals with coronary heart disease and 68 000 controls, people who had a variant of the MTHFR gene that is associated with 20% higher blood homocysteine did not have an increased risk of developing coronary heart disease. (The MTHFR gene is responsible for methylene tetrahydofolate reductase, which uses folate to break down and remove homocysteine.)
The authors say: "The discrepancy between the overall results in the unpublished and the published datasets is too extreme to be plausibly dismissed as a chance finding. Some studies, particularly if small, might have been prioritised for publication by investigators, referees, or editors according to the positivity of their results and some may have been liable to other methodological problems that bias the average of all results. To avoid such biases, we chiefly emphasise the new results from the previously unpublished datasets."
The authors conclude: "The magnitude of the effect of publication bias is substantial and in addition to distorting the association of MTHFR with CHD [coronary heart disease] in published studies, publication bias may also help explain the discrepant findings recently reported for MTHFR and stroke." Importantly, the lack of any link of disease with high homocysteine levels in the 50,000 unpublished heart disease cases with the MTHFR genetic variant is consistent with the null results from 10 large trials testing the effect on coronary heart disease of 5 years of folic acid treatment in 50,000 participants. Hence, both the genetic studies and the trials argue against the use of folic acid supplements as a means of reducing coronary heart disease risk.
Funding: Supported by grants from the British Heart Foundation and UK Medical Research Council to the University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), and the Oxford BHF Centre for Research Excellence (JCH). No funding bodies played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The Clinical Trial Service Unit has a policy of not accepting honoraria or other payments from the pharmaceutical industry, except for reimbursement of costs to participate in scientific meetings (RCl, DAB, SP, JCH, RCo, RP). PV and MDK are employees of Unilever R&D Vlaardingen, The Netherlands. Unilever makes no claims regarding B-vitamins, homocysteine, and CVD on their food products, and PV and MDK have worked on the paper due to their expertise and data from previous academic life. PV and MDK therefore do not consider this to be a competing interest but declare it for reasons of transparency. HH is an employee of deCode, a biotechnology company that produces genetic testing services. JD and RCo are on the Editorial Board of PLoS Medicine. All other authors have declared that no competing interests exist.
Citation: Clarke R, Bennett DA, Parish S, Verhoef P, Dötsch-Klerk M, et al. (2012) Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias. PLoS Med 9(2): e1001177. doi:10.1371/journal.pmed.1001177
CONTACT:
Robert Clarke
Clinical Trial Service Unit
University of Oxford
Richard Doll Building, Old Road Campus
Roosevelt Drive
Oxford, OX3 7LF
United Kingdom
44-1865-743743/743822
robert.clarke@ctsu.ox.ac.uk
Journal
PLoS Medicine