Homocysteine, Folic Acid and the Heart: an Association Unravels

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We may have the final word on homocysteine: higher blood levels of the amino acid don’t raise people’s risk of heart disease after all.

Several decades ago, studies of children born with an unusual genetic defect, which led them to make excessive amounts of homocysteine, found that they also suffered from higher rates of heart disease. That led researchers to wonder whether the amino acid, which is critical to many proteins, was an independent risk factor for heart problems.

Because people with high levels of homocysteine also tend to have low levels of B vitamins, doctors speculated that giving them supplements of the B vitamin folic acid, which helps break down homocysteine, would protect them from heart attacks. But research failed to bear out the theory: in a seven-year study of 12,064 heart-attack survivors, published in 2010, participants who took daily supplements of folic acid and vitamin B12 had 28% lower levels of homocysteine in the blood, but no reduction in heart events or stroke, compared with people taking placebo.

Other studies investigating the connection between homocysteine and heart disease were inconclusive; some showed that higher levels of the amino acid were linked to an increased risk of problems, while others failed to show a strong connection.

MORE: Folic Acid, B12 Don’t Lower Heart Disease Risks

In the latest study, led by Robert Clarke, of the University of Oxford Clinical Trials Service Unit, researchers took advantage of genetic studies to clarify the relationship. Clarke and his team studied 116,000 patients, some of whom had heart problems and all of whom had genetic analysis done for mutations in a gene involved in homocysteine production.

The genetic aberration led to a 20% increase in the participants’ blood homocysteine levels, compared with those without the genetic change, but they were not at any increased risk of having heart disease. “These results settle the homocysteine question fairly reliably,” says Clarke, whose study was published in PLoS Medicine. “These people have a lifelong increase of 20% in their homocysteine levels, but we convincingly showed there is no association between this genetic variant and cardiovascular disease risk. We think this closes the door on that chapter.”

Due to the lack of strong evidence favoring a connection, the American Heart Association (AHA) does not consider homocysteine a risk factor for heart disease, nor does it discuss folate as way to protect the heart. “There is no evidence to recommend [folic] acid supplementation for heart disease,” says Dr. Donna Arnett, president-elect of the AHA and chair of the department of epidemiology at University of Alabama Birmingham. “This study closes the door on that.”

Subgroups of patients, however, may still benefit from folate for heart. (And, of course, pregnant moms should take it to lower the risk of neural tube defects.) Arnett says that the elderly tend to lose folate as they age, and supplementing their deficiencies may lower their risk of heart disease as well, but there are no studies confirming this theory yet.

MORE: Low Vitamin B12 Linked to Smaller Brains and Cognitive Decline

In the meantime, the results serve as a reminder that supplements aren’t always effective at preventing disease, and as appealing as they might seem, their effect isn’t often supported by solid scientific evidence.

Alice Park is a writer at TIME. Find her on Twitter at @aliceparkny. You can also continue the discussion on TIME’s Facebook page and on Twitter at @TIME.