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Did you know DNA influences your risk of folate deficiency?

Folic acid, birth defects and genes

Folic acid. If pregnancy is the first thing that comes to your mind when you hear these words, public health campaigns all over the world have been successful. Low folic acid levels are linked to birth defects of the brain, spine and the spinal column known as neural tube defects. Given that it’s a nutrient, one might think it would be easy enough to regulate folic acid levels. Yet, unlike other well-recognized risk factors of birth defects such as the age of the mother or lifestyle choices (such as drinking and smoking), the one element that controls folic acid levels appears to be out of our hands. That is genetics, and inheriting changes in two genes, MTHFR and MTHFD1 can control the levels of folate in our bodies.

Folate or folic acid is a B vitamin (B9) involved in making new cells and maintaining them, and in building DNA and amino acids. It is essential for the production of red blood cells and white blood cells. Folate is also responsible for preventing changes to the DNA that can cause cancer. Once absorbed, folate is converted to several different forms in our bodies and many enzymes are involved in this processing. The MTHFR and MTHFD1 genes encode two of these enzymes. Genetic variants (small changes in the DNA) in these genes influence folic acid levels.

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The MTHFD1 gene encodes a tri-functional folate-converting enzyme. People with a variant of this gene, called rs2236225 A, produce an enzyme that is much less efficient at converting folate. The resulting low folate levels are linked to a higher risk of birth defects, second trimester pregnancy loss and placental abruption, when the placenta separates from the body before the baby is born. Those with a variant of MTHFR, the second gene linked to low folate levels, also make an enzyme that is much less active. People with one defective copy of MTHFR can process about 65% of the folate they ingest, whereas people with two defective copies process only about 30%. The effects of this MTHFR variant reach far beyond pregnancy-associated risks, as low folate levels can also lead to the buildup of homocysteine. Elevated homocysteine levels are a risk factor for many other conditions, such as coronary artery disease, schizophrenia and autism.

Folic acid may appear to be more relevant to adult women (particularly during pregnancy), but it is also essential in children and male adults. Folate deficiency also causes megaloblastic anemia, characterized by large abnormal red blood cells. Early symptoms of folate deficiency include fatigue, irritability, heart palpitations, headaches, trouble concentrating and shortness of breath. Isolated folate deficiency is usually rare, and it often occurs together with other nutrient deficiencies, especially vitamin B12 deficiency, suggesting that your diet may be to blame. Eggs, fish, legumes and leafy green vegetables are great sources of folate. More dietary sources and recommended dietary allowances of this vitamin are found at the end of the article.

While it is hard to take in too much folate from food, folic acid toxicity is a concern if you are taking a supplement or eating a lot of fortified foods. Digestive problems, nausea, loss of appetite, bloating, unpleasant taste in the mouth, sleep disturbance and depression are some of the more moderate symptoms of folate toxicity. There can also be serious side effects, such as psychotic behaviour, numbness, trouble concentrating, confusion and even seizures. Large doses of folic acid can also permanently damage the nervous system. You should be able to avoid these adverse effects by simply keeping your folate intake under the recommended upper limit of 1000 mcg a day for adults. Tolerable upper limits for other age groups are shown at the end of this article. 

Folic acid may protect us from cardiovascular disease and from mental disorders, like schizophrenia and Alzheimer’s, yet loading up on folic acid without considering your genetic background is not such a good idea. According to a recent study, giving extra folic acid to mice with the MTHFD1 variant increased the incidence of birth defects. While it is entirely possible that this finding may not be directly applicable to people, it tells us that genetics can dictate the benefits of folic acid. Rather than taking a chance with your well being or maybe risking the health of your unborn baby, you might consider checking which variants you carry in your MTHFR and MTHFD1 genes before heading out to the nutrition store.

Recommended dietary allowances for folate.

Recommended dietary allowances are listed as micrograms of dietary folate equivalents (mcg DFE) to take into account the higher bioavailability of folic acid than that of food folate. 1 mcg of food folate is equal to 1 mcg DFE, but only 0.5-0.6 mcg of fortified foods or dietary supplements is required to achieve the same 1 mcg DFE.  For infants from birth to 12 months, an adequate intake is shown, which is equivalent to the mean intake of folate in healthy, breastfed infants.

Age Male Female Pregnancy Lactation
0–6 months 65 mcg DFE 65 mcg DFE
7–12 months 80 mcg DFE 80 mcg DFE
1–3 years 150 mcg DFE 150 mcg DFE
4–8 years 200 mcg DFE 200 mcg DFE
9–13 years 300 mcg DFE 300 mcg DFE
14+ years 400 mcg DFE 400 mcg DFE 600 mcg DFE 500 mcg DFE

Selected foods sources of folate and folic acid.

The Daily Value (DV) for folate is 400 mcg for adults and children age 4 and older. This DV was developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet.

Food mcg DFE per serving Percent DV
Beef liver, braised, 3 ounces 215 54
Spinach, boiled, ½ cup 131 33
Black-eyed peas (cowpeas), boiled, ½ cup 105 26
Breakfast cereals, fortified with 25% of the DV* 100 25
Rice, white, medium-grain, cooked, ½ cup* 90 23
Asparagus, boiled, 4 spears 89 22
Spaghetti, cooked, enriched, ½ cup* 83 21
Brussels sprouts, frozen, boiled, ½ cup 78 20
Lettuce, romaine, shredded, 1 cup 64 16
Avocado, raw, sliced, ½ cup 59 15
Spinach, raw, 1 cup 58 15
Broccoli, chopped, frozen, cooked, ½ cup 52 13
Mustard greens, chopped, frozen, boiled, ½ cup 52 13
Green peas, frozen, boiled, ½ cup 47 12
Kidney beans, canned, ½ cup 46 12
Bread, white, 1 slice* 43 11
Peanuts, dry roasted, 1 ounce 41 10
Wheat germ, 2 tablespoons 40 10
Tomato juice, canned, ¾ cup 36 9
Crab, Dungeness, 3 ounces 36 9
Orange juice, ¾ cup 35 9
Turnip greens, frozen, boiled, ½ cup 32 8
Orange, fresh, 1 small 29 7
Papaya, raw, cubed, ½ cup 27 7
Banana, 1 medium 24 6
Yeast, baker’s, ¼ teaspoon 23 6
Egg, whole, hard-boiled, 1 large 22 6
Vegetarian baked beans, canned, ½ cup 15 4
Cantaloupe, raw, 1 wedge 14 4
Fish, halibut, cooked, 3 ounces 12 3
Milk, 1% fat, 1 cup 12 3
Ground beef, 85% lean, cooked, 3 ounces 7 2
Chicken breast, roasted, ½ breast 3

*Fortified with folic acid as part of the folate fortification program.

Tolerable upper intake levels for folic acid.

These upper limits apply to folic acid – the synthetic form of folate available in dietary supplements and fortified foods. Breast milk, formula and food should be the only sources of folate for infants. These upper limits do not apply to individuals  taking high doses of folic acid under medical supervision.

Age Male Female
0–12 months Not possible to establish Not possible to establish
1–3 years 300 mcg 300 mcg
4–8 years 400 mcg 400 mcg
9–13 years 600 mcg 600 mcg
14–18 years 800 mcg 800 mcg
19+ years 1,000 mcg 1,000 mcg

Recommended dietary allowances, food sources and tolerable upper limits are obtained from the Folate Dietary Supplement Fact Sheet (National Institutes of Health).

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