Homocysteine as a Cause of Ischemic Heart Disease: The Door Remains Open

To the Editor:Clarke et al. conclude that serum homocysteine does not cause ischemic heart disease (IHD) (1), an assessment they based on 19 new studies that showed no increased IHD risk in individuals with the MTHFR [methylenetetrahydrofolate reductase (NAD(P)H)] polymorphism, compared with those without. In excluding results from 86 earlier publications that collectively did show an increased risk, they claimed that the reports of increased risk were due to publication bias (1). The 19 new studies were incorrectly described as “unpublished,” the implication being that they caused the publication bias (preferential reporting of small studies with positive results over small studies with negative results), but they were new analyses on previously stored samples or data.MTHFR polymorphism studies are used to investigate whether homocysteine and IHD are causally linked, because moderately increased homocysteine concentrations can be caused by, in certain environments (e.g., low folate), the C-to-T mutation in the MTHFR gene. The study of IHD risk in people with the mutation (TT) and without it (CC) provides a natural randomized experiment of the relationship of homocysteine to IHD (2).We performed 2 analyses to address the issue: ( a ) an overall metaanalysis of the 19 new studies and the 86 earlier publications to determine whether any effect was apparent when all available data were …