The MTHFR gene provides the instructions for making an enzyme of the same name: methylenetetrahydrofolate reductase (MTHFR). That enzyme works with the B vitamin folate to decrease homocysteine levels in the blood by converting it to another amino acid, explains Charis Eng, MD, PhD, chair of the Genomic Medicine Institute at the Cleveland Clinic.
Like many genes, the MTHFR gene has variants which may change the way the MTHFR enzyme works. That, in turn, can elevate homocysteine levels in your blood. Homocysteine is an amino acid which, when broken down, is used to make other substances to be used by your body, according to the U.S. National Library of Medicine (NLM)
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Gene variants in general are very common and help determine traits like hair and eye color. Mutations are changes in genes that are less common, per the Centers for Disease Control and Prevention (CDC).
What Are MTHFR variants?
The most common MTHFR variant is called C677T, according to a July 2015 article in the journal Circulation.
People who have two copies of the C677T variant (one from each parent) are considered "homozygous" for the variant; those with one copy are "heterozygous."
A subset of those with the homozygous variant have reduced enzyme activity and higher homocysteine levels, Dr. Eng says. People with the heterozygous form (i.e., just one copy) have normal homocysteine levels and don't have any disease, she adds.
Another common variant of MTHFR is A1298C. People who have certain variants may also have reduced enzyme functions which allows the build up of homocysteine.
While MTHFR variants are linked with pregnancy complications and neural tube birth defects, health organizations recommend against genetic testing for these variants. Be aware that claims that folic acid is unsafe for people with MTHFR variants are incorrect. "Your body can safely and effectively process all different types of folate, including folic acid" if you have this genetic variant, per the CDC. All pregnant people — regardless of their MTHFR variant status — should take folic acid, the only type of folate that's been proven to prevent neural tube defects, throughout pregnancy.
Symptoms of MTHFR Variants
There are no intrinsic MTHFR gene variant symptoms. That said, variants can be associated with high or normal homocysteine levels which have been linked with different health conditions.
Research is limited, however, and hasn't shown conclusively that the variant actually causes the health condition.
"When something is so common, you need studies of 10,000 or 100,000 cases and controls to make firm conclusions," Dr. Eng says. Existing studies are much smaller.
The specific conditions related to a variant vary depending on which mutation you have. Again, the research on these connections is still preliminary and the major common denominator is high homocysteine levels.
Conditions that have been linked with the C677T variant include:
- Homocysteinemia, a mild and widespread elevation in homocysteine levels
- Homocystinuria, which is a rare condition marked by very high levels of homocysteine. This can lead to cardiovascular disease in teens and young adults. It also increases the risk of blood clots and affect eyes and joints.
- Age-related hearing loss
- Alopecia areata, an autoimmune condition which causes hair loss
- Pregnancy complications such as preeclampsia (high blood pressure) and miscarriages. (Researchers suspect that these complications may actually cause high homocysteine levels rather than the other way around, according to the article in Circulation.)
- Neural tube birth defects like anencephaly (when parts of the baby's brain and skull are missing) and spina bifida (which affects the spine and spinal cord).
- Heart disease including heart attack, stroke, peripheral artery disease and atherosclerosis (coronary artery disease)
- Blood clots
- Certain cancers including breast and ovarian
If you have an MTHFR variant but no abnormalities in homocysteine levels, your health should not be affected. The gene has also not been connected with autism or menopause. Nor do variants affect estrogen levels.
There are no specific risk factors for different MTHFR variants, Dr. Eng says.
But the prevalence does vary with different ethnic groups — per the Circulation article, the MTHFR C677T mutation is present in about 20 to 40 percent of people who are white or of Hispanic descent in the U.S. and 1 to 2 percent of Black individuals. About 8 to 20 percent of people in North America, Europe and Australia have two copies of the C677T mutation.
The A1298C variant is found in 7 to 14 percent of people in North America, Europe and Australia, 4 to 5 percent of Hispanic people and 1 to 4 percent of Asian people, including Chinese people.
Homocysteine levels can also be affected by dietary deficiencies of vitamins B 6 and 12 and folic acid, low thyroid hormone levels, kidney failure as well as obesity, diabetes, high blood pressure or cholesterol, among others.
Diagnosis and Testing
Testing for MTHFR variants is rarely necessary and testing positive for a variant is meaningless.
Instead, if doctors suspect a problem, they should measure actual homocysteine levels, Dr. Eng says. There's nothing you can do about a gene variant in MTHFR. There are, however, ways to change homocysteine levels, namely folic acid and B12 supplementation. There are also tests for folic acid, B6 and B12.
Home tests that claim to test for MTHFR mutations are equally unnecessary. If you do feel that an MTHFR genetic test is necessary, Dr. Eng suggests talking to a genetic counselor.
According to the Circulation article, the only group that may benefit from testing are individuals under the age of 20 or 30 who've had a heart attack, stroke or blood clot which may indicate the condition homocystinuria. Other than this, assume that MTHFR tests are a scam. Tests for homocysteine, though, are not.
Many organizations have concluded that there's no reason to test for variants, including the U.S. Preventive Services Task Force, the American Academy of Family Physicians, the American College of Medical Genetics and the American College of Obstetricians and Gynecologists.
Genetic tests in general are not recommended randomly for all pregnant women, says Christine Greves, MD, an ob-gyn at Winnie Palmer Hospital for Women & Babies in Orlando. Instead, work with an expert to find out if one is necessary. "Research changes all the time and it's helpful to have a guide through an area of the unknown," she says.
There are no treatments for MTHFR variants — and, in fact, these variants do not actually don't need to be treated anyway. There are, however, treatments for low homocysteine levels and for conditions shown to be linked to these variants. Typically, homocysteine levels can be lowered with vitamins B6, B12, folate or folic acid supplementation.
Conditions are treated the same regardless of whether you have a variant of the gene. Lowering homocysteine levels haven't been shown to a lower risk of heart disease or blood clots.
MTHFR Variants and Pregnancy
Having an MTHFR variant, or suspecting you do, doesn't mean anything will go wrong with your pregnancy or baby. Not having enough folic acid, however, can contribute to neural tube defects.
That's why all people who are pregnant (as well as women of reproductive age and those who are breastfeeding) should take a prenatal vitamin containing 400 micrograms of folic acid every day of their pregnancy regardless of MTHFR status, per the CDC. This can reduce but not eliminate the chances of neural tube defects as only about 20 percent of women who bear a child with a neural tube defect have problems with homocysteine. Folic acid is the only type of folate that can reduce this risk, according to the CDC.
There's been some confusion about whether pregnant people should be taking prenatal vitamins containing folic acid or another supplement known as MTHF folate. While there are many forms of vitamin B9 (aka folate), only folic acid, which is the synthetic form, can reduce the risk of neural tube defects, according to the CDC. (Any supplements with folate, regardless of its form, are synthetic, even ones that have "natural food folate" on the label, per the CDC. This includes 5-MTHF folate.)
The American College of Obstetrics and Gynecology and the Centers for Disease Control and Prevention recommend taking folic acid.
If a woman has a history of neural tube defects, doctors may recommend as much as 4,000 micrograms of folic acid, Dr. Greves says. As always, if you are unsure about your best approach with supplements, reach out to your health care provider for a recommendation.
Diet and Supplementation
While some MTHFR variants are linked with reduced homocysteine levels, so can not getting enough folic acid, vitamin B6 and vitamin B12 in your diet. Folic acid is plentiful in fruits and vegetables (look for green leafy vegetables like spinach), fortified breads and cereals, legumes (lentils, chickpeas) and beans.
Folic acid supplementation may also be recommended for certain health conditions. Supplementation may prevent strokes in people who have preexisting cardiovascular disease, per an October 2017 review in the American Journal of the Medical Sciences.
Being positive for a variant does not mean you need to avoid any foods or alcohol.
Having an MTHFR gene variant doesn't mean you have a medical condition, nor that you are at risk for one. That's why routine testing is not recommended.
Some variants are associated with elevated levels of the amino acid homocysteine, which can have health consequences. But higher levels of homocysteine have other causes as well. Doctors sometimes test for homocysteine deficiency so they can correct it by adding folic acid, vitamin B6 and vitamin B12. Pregnant people, in particular, are advised to take 400 micrograms of folic acid while expecting.
- National Library of Medicine: “MTHFR gene”
- National Library of Medicine: “Homocysteine Test”
- Circulation: “Homocysteine and MTHFR Mutations”
- Centers for Disease Control and Prevention: “MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects”
- European Journal of Medicine Genetics: “Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases”
- Centers for Disease Control and Prevention: “Facts about Anencephaly”
- BioScience Trends: “Association of MTHFR 677C>T polymorphism with pregnancy outcomes in IVF/ICSI-ET recipients with adequate synthetic folic acid supplementation”
- Onco Targets and Therapy: “MTHFR C677T polymorphism and breast, ovarian cancer risk: a meta-analysis of 19,260 patients and 26,364 controls”
- Cleveland Clinic: “A Genetic Test You Don’t Need”
- American Journal of Clinical Nutrition: “The 677C→T variant of MTHFR is the major genetic modifier of biomarkers of folate status in a young, healthy Irish population”
- Genetics in Medicine: “ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing”
- American College of Obstetrics and Gynecology Practice Bulletin: “Neural Tube Defects”
- The American Journal of the Medical Sciences: “Folic Acid Supplementation for Stroke Prevention in Patients With Cardiovascular Disease”
- CDC: "General Information About NTDs, Folic Acid, and Folate"
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