Is Homocysteine a CHD Risk Factor? The Genetic View
- Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias
Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication BiasClarke R, Bennett DA, Parish S, et al
PLoS Med. 2012;9:e1001177
SummaryHomocysteine has undergone intense scrutiny over the past decade because it meets many of the criteria by which clinically relevant cardiovascular risk factors are judged. However, attempts to lower plasma homocysteine in the general population have resulted in relatively small reductions in coronary heart disease (CHD) risk.
The enzyme methylene tetrahydrofolate reductase, encoded by the MTHFR gene, uses folate to metabolize and lower plasma homocysteine levels. Clinical trials in patients with a common MTHFR polymorphism that reduces enzyme efficiency have shown higher plasma homocysteine levels and a higher risk for CHD, suggesting a link between folate levels and homocysteine metabolism. Yet multiple clinical trials have demonstrated that homocysteine reduction with supplemental folate fails to reduce cardiovascular events.
In an attempt to better understand the relationships among homocysteine levels, folic acid, and CHD risk, this meta-analysis evaluated data from 19 unpublished datasets comprising a total of 48,175 CHD cases and 67,961 controls in which multiple genetic variants were measured, including the MTHFR polymorphism. The conclusion from this very large dataset is that lifelong moderate homocysteine elevation has little or no effect on CHD risk.
ViewpointThis study provides definitive proof that mild-to-moderate elevations of homocysteine, such as those seen in patients with the MTHFR polymorphism, are not associated with increased cardiovascular risk. This also likely explains why folic acid supplementation did not reduce cardiovascular events in multiple prospective, long-term, placebo-controlled clinical trials in the general population in whom homocysteine levels were not severely elevated.
Prior to the failure of these clinical trials to demonstrate a benefit of folic acid supplementation, many clinicians measured homocysteine levels and, if elevated, would recommend folic acid supplementation for their patients. Later, even though folic acid was shown to be ineffective in reducing CHD risk in these patients, it was thought that other therapies to lower homocysteine may still be proven to reduce cardiovascular events. Given the data from this meta-analysis, this outcome seems unlikely.
However, there have been concerns that drugs that raise homocysteine levels, such as fibrates, may have a detrimental effect on cardiovascular risk. Fibrates, especially fenofibrate, can increase homocysteine levels by approximately 50%; this increase has been linked to suppression of apolipoprotein A1 synthesis, which, in turn, leads to reduced levels of high-density lipoprotein.
Although this meta-analysis found no link between the MTHFR polymorphism that increases homocysteine and CHD risk, the study does not rule out the possibility that fibrate-induced increases in homocysteine are not harmful.[5,6] Nor does it address the extreme elevations of homocysteine linked to venous thrombosis and accelerated atherosclerosis seen in other genetic causes of hyperhomocysteinemia.
Nevertheless, this study provides reassurance for the 15%-45% of the population with the MTHFR polymorphism associated with increased homocysteine levels that their risk for CHD is not significantly increased. Note that, even in these individuals, folic acid supplementation may still be advisable in some cases, such as in women of child-bearing age to avoid potential neural tube defects that are associated with low folic acid levels.
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