MTHFR, Homocysteine and Heart Disease: What the Evidence Really Shows

Heart and circulatory disease is one of the leading causes of death in Ireland. Most prevention focuses on blood pressure, cholesterol, smoking, diabetes and weight, and for good reason: these have the strongest evidence. You'll also read online that homocysteine is a hidden risk factor that doctors ignore, and that MTHFR variants put large numbers of people at risk. The real picture is more nuanced, and worth understanding properly.

What is homocysteine?

Homocysteine is an amino acid made in the body as part of the methylation cycle. Folate, vitamin B12 and vitamin B6 are needed to convert it into other substances, so low intake or low levels of these vitamins can cause it to build up. Kidney disease, smoking, heavy drinking, an underactive thyroid, some medicines and age can also raise it.

What observational studies show

Large studies that follow people over time have found that higher homocysteine is associated with a higher risk of heart disease and stroke. The Homocysteine Studies Collaboration, which pooled data from many such studies in 2002, found that 25% lower homocysteine was associated with roughly 11% lower risk of coronary heart disease and 19% lower risk of stroke, after adjusting for other risk factors.

But association isn't the same as cause. People with higher homocysteine are also more likely to smoke, have kidney problems or eat a poorer diet, and these can't always be fully separated out.

What happened when trials lowered homocysteine

The real test is whether lowering homocysteine with B vitamins reduces heart attacks and strokes. Many large randomised trials have tried this:

• B vitamins lowered homocysteine reliably, typically by around a quarter.
• Heart attacks and deaths didn't fall. A Cochrane review of these trials found that homocysteine-lowering B vitamins did not reduce heart attacks or death from any cause.
• Stroke may be a partial exception. The same review found a possible small reduction in stroke. Much of this comes from the China Stroke Primary Prevention Trial, in which adults with high blood pressure, in a population without folic acid fortification, had fewer first strokes when folic acid was added to their blood pressure medicine.

So homocysteine may be more of a marker of risk than a major cause of heart attacks, at least in people who already get enough folate. Its role in stroke is discussed in our separate stroke article.

How much does MTHFR matter?

People with two copies of the MTHFR C677T variant (TT) tend to have somewhat higher homocysteine, particularly when folate intake is low. But large genetic studies have found little or no extra heart disease risk from MTHFR variants in populations with good folate intake. That's one reason MTHFR testing isn't recommended for assessing heart risk.

Should you get homocysteine tested?

Homocysteine isn't part of routine heart risk checks in Ireland, and guidelines don't recommend testing everyone. It may be worth discussing with your GP if you have:

• signs of B12 or folate deficiency
• heart disease or stroke at a young age without obvious risk factors
• a family history of very early heart disease, stroke or blood clots
• kidney disease, or long-term use of medicines that affect B vitamins

If homocysteine is high, the first step is finding out why, including checking B12 and folate, rather than just adding supplements.

What reduces heart risk most

These steps have strong evidence for preventing heart attacks and strokes:

• Stop smoking. It's the single biggest change most smokers can make. The HSE QUIT service offers free support.
• Know your blood pressure and treat it if it's high. Many pharmacies check it for free or for a small charge.
• Check cholesterol and blood sugar, especially from your 40s or earlier with a family history.
• Move more. Aim for at least 150 minutes of moderate activity a week, such as brisk walking.
• Eat well. A Mediterranean-style diet with vegetables, fruit, wholegrains, beans, nuts, olive oil and oily fish, and less processed meat and salt. These foods are also natural sources of folate, B6 and B12.
• Keep alcohol low and aim for a healthy weight.
• Take prescribed medicines such as statins or blood pressure tablets as directed.

Folate, vitamin B6 and vitamin B12 contribute to normal homocysteine metabolism, and making sure you get enough is sensible. But B vitamins aren't a substitute for the steps above.

This article is for general information and is not medical advice. Please speak to your GP about your heart health, and don't stop prescribed medicines in favour of supplements.