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Metabolomics/Nutrition/Folate

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Folic acid (also known as vitamin B9[1] or folacin) and folate (the naturally occurring form), as well as pteroyl-glutamic acid|L-glutamic acid and pteroyl-glutamate|L-glutamate, are chemical formula|forms of the water-soluble B vitamins|vitamin B9. Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver.[2]

Vitamin B9 (folic acid and folate inclusive) is essential nutrient|essential to numerous physiology|bodily functions ranging from nucleotide biosynthesis to the methylation|remethylation of homocysteine. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in biological reactions involving folate.[3] It is especially important during periods of rapid cell division and cell growth|growth. Both children and adults require folic acid to produce healthy red blood cells and prevent anemia.[4] Folate and folic acid derive their names from the Latin word Wiktionary:folium|folium (which means "leaf"). Leafy vegetables are a principal source, although in Western diets fortified cereals and bread may be a larger dietary source.

A lack of diet (nutrition)|dietary folic acid leads to folate deficiency (FD). This can result in many health problems, most notably neural tube defects in developing embryos. Low folate can also lead to homocysteine accumulation as a result of one carbon metabolism mechanism methylation being impaired.[3] DNA synthesis and repair are impaired and this could lead to cancer development.[3] Supplementation in patients with ischaemic heart disease may however lead to increased rates of cancer and all-cause mortality.[5]

A 2003 opinion article in the New York Times [6] named micronutrients, especially folic acid, the "world's most luscious food" since absence of folic acid and a handful of other micronutrients causes otherwise-preventable deformities and diseases, especially in fetal development. Adding folic acid and micronutrients to the food supply of developing countries would have a greater impact than any other single action in improving world health.

Dietary reference intake

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Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. 1 DFE is defined as 1 μg (microgram) of dietary folate, or 0.6 μg of folic acid supplement.

Women Pregnant Women Men
RDA[7] 400 µg DFE 600 µg DFE 400 µg DFE
UL[7] 1000 µg DFE 1000 µg DFE 1000 µg DFE

Folate in foods and other sources

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Certain foods are very high in folate:

  • Leafy vegetables such as spinach, asparagus, turnip|turnip greens,
  • Legumes such as dried or fresh beans, peas and lentils
  • Liver (food)|Liver and liver products also contain high amounts of folate.
  • baker's yeast,
  • fortified grain products (pasta, cereal, bread), Some breakfast cereals (ready-to-eat and others) are fortified with 25% to 100% of the recommended dietary allowance (RDA) for folic acid.
  • sunflower seeds

Moderate amounts:

  • certain fruits (orange juice, canned pineapple juice, cantaloupe, honeydew melon, grapefruit juice, banana, raspberry, grapefruit, strawberry) and vegetables (beets, corn, tomato juice, vegetable juice, broccoli, brussels sprouts, romaine lettuce, bok choy),[8] beer.[9]

A table of selected food sources of folate and folic acid can be found at the USDA National Nutrient Database for Standard Reference.[10] Folic acid is added to grain products in many countries, and in these countries fortified products make up a significant source of the population's folic acid intake[11]. Because of the difference in bioavailability between supplemented folic acid and the different forms of folate found in food, the dietary folate equivalent (DFE) system was established. 1 DFE is defined as 1 μg of dietary folate, or 0.6 μg of folic acid supplement. This is reduced to 0.5 μg of folic acid if the supplement is taken on an empty stomach.[12]

Folic acid naturally found in food is susceptible to high heat, UV, and is soluble in water.[13] It is heat labile in acidic environments and may also be subject to oxidation.[13]

Some meal replacement products do not meet the folate requirements as specified by the RDAs.[14]

Conversion to biologically active derivatives

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All the biological functions of folic acid are performed by tetrahydrofolate and other derivatives. Their biological availability to the body depends upon dihydrofolate reductase action in the liver. This action is unusually slow in humans being less than 2% of that in rats. Moreover, in contrast to rats, an almost 5-fold variation in the activity of this enzyme exists between humans.[2] Due to this low activity it has been suggested that this limits the conversion of folic acid into its biologically active forms "when folic acid is consumed at levels higher than the Tolerable Upper Intake Level (1 mg/d for adults)."[2]

History

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In the 1920s scientists believed that folate deficiency and anemia were the same condition.[15] A key observation by researcher Lucy Wills in 1931 led to the identification of folate as the nutrient needed to prevent anemia during pregnancy. Dr. Wills demonstrated that anemia could be reversed with brewer's yeast. Folate was identified as the corrective substance in brewer's yeast in the late 1930s and was first isolated in and extracted from spinach leaves by Mitchell and others in 1941.[16] Bob Stokstad isolated the pure crystalline form in 1943, and was able to determine its chemical structure while working at the Lederle Laboratories of the American Cyanamid Company[17]. This historical research project, of obtaining folic acid in a pure crystalline form in 1945, was done by the team called the "folic acid boys," under the supervision and guidance of Director of Research Dr. Yellapragada Subbarao, at the Lederley Lab, Pearl River, NY.[18] This research subsequently led to the synthesis of the antifolate Aminopterin, the first ever anti-cancer drug, the clinical proof of its efficacy was proven by Dr. S. Farber in 1948. In the 1950s and 1960s scientists began to discover the biochemical mechanisms of action for folate.[15] In 1960 experts first linked folate deficiency to neural tube defects.[15] In the late 1990s US scientists realized that despite folate being available in foods and in supplements, there was still a challenge for people to meet their daily folate requirements, and that is when the US implemented the folate fortification program.[15]

Biological roles

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Image:Folat.svg|thumb|A diagram of the chemical structure of folate.

DNA and cell division

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Folate is necessary for the production and maintenance of new cell (biology)|cells, for DNA synthesis and RNA synthesis, and for preventing changes to DNA and thus preventing cancer.[19] It is especially important during periods of rapid cell division and growth such as infancy and pregnancy. Folate is needed to carry one carbon groups for methylation reactions and nucleic acid synthesis (most notably thymine, but also purine bases).[20] Thus, folate deficiency hinders DNA synthesis and cell division, affecting hematopoietic cells and neoplasms the most because of rapid cell division. RNA transcription, and subsequent protein synthesis, are less affected by folate deficiency, as the mRNA can be recycled and used again (as opposed to DNA synthesis where a new genomic copy must be created). Since folate deficiency limits cell division, erythropoiesis, production of red blood cells is hindered and leads to megaloblastic anemia which is characterized by large immature red blood cells. This pathology results from persistently thwarted attempts at normal DNA replication, DNA repair, and cell division, and produces abnormally large red cells called megaloblasts (and hypersegmented neutrophils) with abundant cytoplasm capable of RNA and protein synthesis, but with clumping and fragmentation of nuclear chromatin. Some of these large cells, although immature (reticulocytes), are released early from the marrow in an attempt to compensate for the anemia.[21] Both adults and children need folate to make normal red and white blood cells and prevent anemia.[22] Deficiency of folate in pregnant women has been implicated in neural tube defects (NTD); therefore, many developed countries have implemented mandatory folic acid fortification in cereals, etc. It must be noted that NTD's occur early in pregnancy (first month) therefore women must have abundant folate upon conception. Folate is required to make red blood cells and white blood cells and folate deficiency may lead to anemia which further leads to fatigue (medical)|fatigue and weakness and inability to concentrate.[23]

Biochemistry of DNA base and amino acid production

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Image:Folicacid-B12.png|thumb|Right|Metabolism of folic acid to produce methyl-vitamin B12

In the form of a series of tetrahydrofolate (THF) compounds, folate derivatives are substrate (biochemistry)|substrates in a number of single-carbon-transfer reactions, and also are involved in the synthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). It is a substrate for an important reaction that involves vitamin B12 and it is necessary for the synthesis of DNA, and so required for all dividing cells.[24]

The pathway leading to the formation of tetrahydrofolate (FH4) begins when folate (F) is redox|reduced to dihydrofolate (DHF) (FH2), which is then reduced to THF. Dihydrofolate reductase catalyses the last step.[25] Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis.

Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. It is important to note that Vitamin B12 is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B12 which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a deficiency of B12 can lead to a methyl-trap of THF and a subsequent deficiency[17]. Thus, a deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency. Another form of THF, formyl-THF or folinic acid) results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Finally, histidine can donate a single carbon to THF to form methenyl-THF.

In other words:

folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF

Overview of drugs that interfere with folate reactions

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A number of drugs interfere with the biosynthesis of folic acid and THF. Among them are the :Category:Dihydrofolate reductase inhibitors|dihydrofolate reductase inhibitors such as trimethoprim, pyrimethamine and methotrexate; the Sulfonamide (medicine)|sulfonamides (competitive inhibitors of 4-aminobenzoic acid in the reactions of dihydropteroate synthetase).

The National Health and Nutrition Examination Survey (NHANES III 1988–91) and the Continuing Survey of Food Intakes by Individuals (1994–96 CSFII) indicated that most adults did not consume adequate folate.[26][27] However, the folic acid fortification program in the United States has increased folic acid content of commonly eaten foods such as breakfast cereal|cereals and cereal|grains, and as a result diets of most adults now provide recommended amounts of folate equivalents.[28]

Health issues

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Human reproduction

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Folic acid is an important nutrient for women who may become Pregnancy|pregnant, because a woman's blood levels of folate fall during pregnancy due to an increased maternal RBC synthesis in the first half of the pregnancy and fetal demands in the second half.[7] The first four weeks of pregnancy (when most women do not even realize they are pregnant) require folic acid for proper development of the brain, skull, and spinal cord.[8] Serious birth defects like neural tube defects are less likely to occur when women take 0.4 mg of folic acid daily.[8] Adequate folate intake during the preconception period, the time right before and just after a woman becomes pregnant, helps protect against a number of congenital malformations including neural tube defects (which are the most notable birth defects that occur from folate deficiency).[29] Neural tube defects (NTDs) result in malformations of the spine (spina bifida), skull, and brain (anencephaly). The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet prior to and during the first month following conception.[30][31] The protective effect of folate during pregnancy goes beyond NTDs. Supplementation with folic acid has been shown to reduce the risk of congenital heart defects, Cleft lip and palate|cleft lip[32], limb defects, and urinary tract anomalies.[33] Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of some serious birth defects. Having enough folic acid supplements in the months before pregnancy is very important to prevent neural tube defects.[34] Taking 400 micrograms of synthetic folic acid daily from fortified foods and/or supplements has been suggested. The RDA for folate equivalents for pregnant women is 600-800 micrograms, twice the normal RDA of 400 micrograms for women who are not pregnant.[35]

A study published by Milunski et al. has indicated that women who took folic acid supplements during the course of pregnancy can dramatically reduce the prevalence of infant neural tube defects by 3.9 times. The prevalence had dropped from 3.5 to 0.9 defects per 1000 births.[36]

Although the recommended folic acid intake for women planning for pregnancy is 400 micrograms per day, the mechanisms and reasons why folic acid prevents birth defects is unknown.[37] It is hypothesized that the insulin-like growth factor 2 gene is differentially methylated and these changes in IGF2 result in improved intrauterine growth and development.[37]

Folate deficiency during pregnancy can increase the risk of preterm delivery, infant low birth weight, and fetal growth retardation.[38] Folate deficiency in the mother increases homocysteine level in the blood which may lead to spontaneous abortion and pregnancy complications such as placental abruption and preeclampsia.[38]

Recently studies have been conducted to test the hypothesis that folic acid supplementation reduces the risk of childhood acute lymphoblastic leukemia, but evidence so far has been weak.[39]

Folic acid may also reduce chromosomal defects in sperm to some extent, which may be relevant for men considering to father a child.[40] A benefit is indicated even for more than 700 mcg folate per day,[40] which though below the tolerable upper intake levels of 1,000 µg/day was 1.8 times the recommended dietary allowance.

It is estimated that approximately 85% of women use folic acid supplements before they become pregnant but only 18% use enough folic acid supplements to meet the current folic acid requirements due to socio-economic challenges facing some women.[41]

Folic acid supplements may even protect the fetus against disease when the mother is battling a disease or taking medications or smoking and pregnancy|smoking during pregnancy.[42]

Heart disease

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An estimated 13,500 deaths occur annually due to folate deficiency's effect on coronary artery disease and the risk of ischemic heart disease and stroke has been reduced by 15% since folate fortification regulations were enforced.[43] Adequate concentrations of folate, vitamin B12, or vitamin B6 may decrease the circulating level of homocysteine, an amino acid normally found in blood. There is evidence that an elevated homocysteine level is an independent risk factor for heart disease and stroke.[44] The evidence suggests that high levels of homocysteine may damage coronary arteries or make it easier for blood clotting cells called platelets to clump together and form a clot.[45] However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce risk of heart disease. The NORVIT trial suggests that folic acid supplementation may do more harm than good.[46]

As of 2006, studies have shown that giving folic acid to reduce levels of homocysteine does not result in clinical benefit. One of these studies suggests that folic acid in combination with B12 may even increase some cardiovascular risks.[47][48][49]

However a 2005 study found that 5 mg of folate daily over a three-week period reduced pulse pressure by 4.7 mmHg compared with a placebo, and concluded that[50]

Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.

Also, as a result of new research, "heart experts" at Johns Hopkins Medical Center reported in March 2008 [51] in favour of therapeutic folate, although they cautioned that it is premature for people to begin to self-medicate by taking high doses of folic acid."

Hyperhomocysteinemia is a predictor of cardiovascular disease and hypertension among children and folic acid is a safe and effective supplement because it reduces serum homocysteine levels as well as systolic and diastolic blood pressure, thus preventing cardiovascular disease in children.[52]

Folic acid supplements may improve the integrity of the vascular endothelium.[53] Folic acid supplements consumed before and during pregnancy may reduce the risk of heart defects in infants.[54] Folic acid supplementation may reduce the risk of children developing metabolic syndrome.[55] Folic acid supplements may worsen the outcomes in patients with cardiovascular disease such as angina and myocardial infarction.[56]

Stroke

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Folic acid appears to reduce the risk of stroke. The reviews indicate only that in some individuals the risk of stroke appears to be reduced, but a definite recommendation regarding supplementation beyond the current recommended daily allowance has not been established for stroke prevention.[57] Observed stroke reduction is consistent with the reduction in pulse pressure produced by folate supplementation of 5 mg per day, since hypertension is a key risk factor for stroke. Folic supplements are inexpensive and relatively safe to use and that is why stroke or hyperhomocysteinemia patients are encouraged to consume daily B vitamins including folic acid.[58]

Cancer

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Folate deficiency decreases intracellular S-adenosylmethionine (SAM) which inhibits cytosine methylation in DNA, activates proto-oncogenes, induces malignant transformations, causes DNA precursor imbalances, misincorporates uracil into DNA, and promotes chromosome breakage; all of these mechanisms increase the risk of prostate cancer development.[59]

The association between folate and cancer appears to be complex.[60] Even though theoretically it has been suggested that folate may help prevent cancer[61] actual trials have found that supplementation increases rates of cancer.[5]

Some investigations have proposed that good levels of folic acid may be related to lower risk of esophageal, stomach, and ovarian cancer, but benefices of folic acid against cancer may depend on when it is taken and on individual conditions. In addition folic acid may not be helpful, and could even be damaging, in people who already are suffering from cancer or from a precancerous condition. Conversely, it has been suggested that excess folate may promote tumor initiation.[62] Folate has shown to play a dual role in cancer development; low folate intake protects against early carcinogenesis but high folate intake promotes advanced carcinogenesis.[63] Therefore public health recommendations should be careful not to encourage too much folate intake.[63]

Diets great in folate are associated with decreased risk of colorectal cancer; some studies show an association which is stronger for folate from foods alone than for folate from foods and supplements,[64] while other studies find that folate from supplements is more effective due to greater bioavailability.[65] A 2007 randomized clinical trial found that folate supplements did not reduce the risk of colorectal adenomas, but do in fact increase the presence of advanced lesions and adenoma multiplicity.[66] Colorectal cancer is the most studied type of cancer in relation to folate and one carbon metabolism and most research studies associate high folate intake with a reduced risk of prostate cancer.[67] However folic acid supplement intake increased advanced colorectal cancer development by 67% in a 14 year European research study involving 520,000 men.[68]

A 2006 prospective study of 81,922 Swedish adults found that diets great in folate from foods, but not from supplements, were associated with a reduced risk of pancreatic cancer.[69]

Most epidemiologic studies suggest that diets high in folate are associated with decreased risk of breast cancer, but results are not uniformly consistent: one broad cancer screening trial reported a potential harmful effect of much folate intake on breast cancer risk, suggesting that routine folate supplementation should not be recommended as a breast cancer preventive,[70] but a 2007 Swedish prospective study found that much folate intake was associated with a lower incidence of postmenopausal breast cancer.[71] A 2008 study has shown no significant effect of folic acid on overall risk of total invasive cancer or breast cancer among women.[72] Folate intake may not have any effect on the risk of breast cancer but may have an effect for women who consume at least 15 g/d of alcohol.[73] Folate intake of more than 300 µg/d may reduce the risk of breast cancer in women who consume alcohol.[73]

In men, folic acid supplementation appears to double the risk of prostate cancer.[74] Recently a clinical trial showed that daily supplementation of 1 mg of folic acid increased the risk of prostate cancer while dietary and blood plasma|plasma folate levels among non vitamin users actually decreased the risk of prostate cancer.[75] The reasons why high levels of folic acid may increase cancer is because of its role in nucleotide synthesis (proliferating neoplastic cells need this and folate receptors are increased in cancers).[76] Folate's role in DNA methylation is important in prostate cancer.[77] Unmetabolized folic acid is associated with a reduction in natural killer cell cytotoxicity which reduces the immune system's ability to defend against malignant cells.[78] However, the study also showed that dietary baseline intake of folate may have inverse effects of prostate cancer.

The cancer drug methotrexate is designed to inhibit the metabolism of folic acid. Folic acid may interact unexpectedly with the cancer drug fluorouracil. The exact mechanism of interaction is unknown.[79]

The low dihydrofolate reductase activity in the liver of humans compared to other animals and so the low conversion of folic acid into its active derivatives might be due to the control of this enzyme by transcription factors such as E2F-1 involved in cell proliferation. It has been suggested that "the low level of DHFR, and the other proteins under the control of E2F-1, in humans may have evolved to hinder the development of cancer. If this is the case, other animals with slow tissue turnover rates, possibly related to long life span, might also have low DHFR activity.[2]

Although the relationship between folate and prostate cancer is not yet clear, there has been suicide gene studies that show a target vector for folate to prostate and nasopharyngeal cancer cells.[80] Growth of tumor cells are significantly inhibited when a folate-linked nanoparticle is injected intratumorally.[80] The mechanism might be due to the interference of transfection and communication failures of intracellular gap junctions.[80]

A Finnish study consisting of 29,133 older male smokers resulted in the observation that prostate cancer risk had no relationship with serum folate levels.[3]

Folic acid supplements prevent mistakes from occurring during DNA replication and repair, for example the mistake of inserting uracils into the DNA.[81] This is a proposed mechanism for folic acid's protection against colorectal cancer.[81]

Folic acid supplements stimulate the PI3k/Akt signaling cascade which leads to improved cell survival but this could be beneficial or harmful for the body because cancer cells may use this pathway to survive.[82] Folic acid may also reduce the levels of PTEN (a tumor suppressor gene), making this relationship even more controversial.[82]

Antifolates

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Folate is important for cells and tissues that rapidly divide.[19] Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. The antifolate methotrexate is a drug often used to treat cancer because it inhibits the production of the active form of THF from the inactive dihydrofolate (DHF). Unfortunately, methotrexate can be toxic,[83][84][85] producing side effects such as inflammation in the digestive tract that make it difficult to eat normally. Also, bone marrow depression (inducing leukopenia and thrombocytopenia), acute renal and hepatic failure have been reported.

Folinic acid, under the drug name leucovorin, is a form of folate (formyl-THF) that can help "rescue" or reverse the toxic effects of methotrexate.[86] Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.[87][88] There have been cases of severe adverse effects of accidental substitution of folic acid for folinic acid in patients receiving methotrexate cancer chemotherapy. It is important for anyone receiving methotrexate to follow medical advice on the use of folic or folinic acid supplements. The supplement of folinic acid in patients undergoing methotrexate treatment is to give non rapidly dividing cells enough folate to maintain normal cell functions. The amount of folate given will be depleted by rapidly dividing cells (cancer) very fast and so will not negate the effects of methotrexate. Low dose methotrexate is used to treat a wide variety of non-cancerous diseases such as rheumatoid arthritis, Lupus erythematosus|lupus, scleroderma, psoriasis, asthma, sarcoidosis, primary biliary cirrhosis, polymyositis, and inflammatory bowel disease.[89] Low doses of methotrexate can deplete folate stores and cause side effects that are similar to folate deficiency. Both high folate diets and supplemental folic acid may help reduce the toxic side effects of low dose methotrexate without decreasing its effectiveness.[90][91] Anyone taking low dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.

While the role in folate as a cancer treatment is well established its long term effectiveness is diminished by cellular response. In response to decreased THF the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase increased concentrations of DHF reductase can overcome the drugs inhibition.

Obesity

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Folic acid increases lipolysis in adipocytes and may have a role in the prevention of obesity and type 2 diabetes.[92] This mechanism involves the beta adrenoceptors in the abdominal adipocytes.[93] Folic acid supplements may reduce the accumulation of cholesterol in the liver and in the blood; this may be due to folic acid's role in incorporating cholesterol into bile acid.[94] In fact folic acid supplements have been shown to increase bile acid production and flow.[95]

Depression

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Some evidence links a shortage of folate with Clinical depression|depression.[96] There is some limited evidence from Randomized controlled trials|randomised controlled trials that using folic acid in addition to antidepressants, specifically selective serotonin reuptake inhibitor|SSRIs, may have benefits.[97] Research at the University of York and Hull York Medical School has found a link between depression and low levels of folate.[98] One study by the same team involved 15,315 subjects.[99] However, the evidence is probably too limited at present for this to be a routine treatment recommendation. Folic acid supplementation affects noradrenaline and serotonin receptors within the brain and this could be the cause of folic acid's possible ability to act as an antidepressant.[100]

Memory and mental agility

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In a 3-year trial on 818 people over the age of 50, short-term memory, mental agility, and verbal fluency were all found to be better among people who took 800 micrograms of folic acid daily, twice the current RDA, than those who took placebo. The study was reported in The Lancet on 20 January 2007.[101]

Schizophrenia

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Folate deficiency may increase the risk of schizophrenia because by increasing homocysteine levels folate also increases interleukin 6 and tumor necrosis factor alpha levels and these two cytokines are involved in the development of schizophrenia.[102] The exact mechanisms involved in the development of schizophrenia are not entirely clear but may have something to do with DNA methylation and one carbon metabolism and these are the precise roles of folate in the body and that is why folate deficiency has been linked to schizophrenia.[103]

Allergic diseases

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There is a relationship between folic acid and allergic diseases.[104] In one study that examined the relationship between serum folate levels and markers of atopy, wheeze, and asthma in 8083 subjects serum folate levels were found to be inversely related to IgE level, atopy, and wheeze in a dose-response relationship.[105] Increased folate levels were also associated with decreased risk of doctor-diagnosed asthma.[106] Folic acid supplementation during late pregnancy is associated with an increased risk of childhood asthma, increased risk of persistent asthma, and poorer respiratory function in young children.[107]

Rheumatoid arthritis

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Folic acid supplementation of 5–27 mg per week has shown to have a protective effect against rheumatoid arthritis.[108]

Fertility

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Folate is necessary for fertility in both men and women. In men, it contributes to spermatogenesis. In women, on the other hand, it contributes to oocyte maturation, implantation, placentation, in addition to the general effects of #Human reproduction|folic acid and pregnancy. Therefore, it is necessary to receive sufficient amounts through the diet, in order to avoid subfertility.[109]

Renal disease

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Folic acid supplements may reduce the risk of children developing renal diseases or injuries such as microalbuminuria.[110]

Type 1 diabetes mellitus

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Type 1 diabetes mellitus patients have lower plasma levels of folic acid and may benefit from folic acid supplements or folic acid fortified food products.[111]

Macular degeneration

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A substudy of the Women's Antioxidant and Folic Acid Cardiovascular Study published in 2009 reports that use of a nutritional supplement that contains folic acid, pyridoxine, and cyanocobalamin decreased the risk of developing age-related macular degeneration by 34%.[112]

Bone health

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It has been hypothesized that folate deficiency can lead to elevated homocysteine levels which in turn lead to an increased risk of bone fractures, osteoporosis, and reduction in BMD but research studies so far show controversial results.[113]

Menopause

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Folic acid supplements help relieve hot flushes in postmenopausal women.[100] Just like in estrogen hormone replacement therapy, folic acid interacts with neurotransmitters (norepinephrine, serotonin) in the brain to reduce hot flushes.[100]

Infectious disease

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Folate deficiency is linked to anemia causing Plasmodium falciparum malaria in areas such as Colombia where malaria has reached endemic proportions.[114]

Bone loss in Parkinson's disease (PD)

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Folate lowers homocysteine (Hcy) levels which in turn prevents bone loss in Parkinson's disease (PD) patients taking levodopa (a psychoactive drug taken to treat Parkinson's disease).[115] Improvements in bone health include increased BMD at the lumbar spine, total femur, and femur shaft.[116]

Folic acid supplements and masking of B12 deficiency

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There has been concern about the interaction between Vitamin B12|vitamin B12 and folic acid.[117] Folic acid supplements can correct the anemia associated with vitamin B12 deficiency.[citation needed] Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage could theoretically occur if vitamin B12 deficiency is not treated. Therefore, intake of supplemental folic acid should not exceed 1000 Kilogram|micrograms (1000 µg = 1 mg) per day to prevent folic acid from masking symptoms of vitamin B12 deficiency. In fact, to date the evidence that such masking actually occurs is scarce, and there is no evidence that folic acid fortification in Canada or the U.S. has increased the prevalence of vitamin B12 deficiency or its consequences.[118]

However, one recent study has demonstrated that high folic or folate levels, when combined with low B12 levels, are associated with significant cognitive impairment among the elderly.[119]

In any case, it is important for older adults to be aware of the relationship between folic acid and vitamin B12, because they are at greater risk of having a vitamin B12 deficiency. Patients 50 years of age or older should ask their physicians to check their vitamin B12 status before taking a supplement that contains folic acid.[120]

Health risk of too much folic acid

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The risk of toxicity from folic acid is low because folate is a water soluble vitamin and is regularly removed from the body through urine.[121] The Institute of Medicine has established a tolerable upper intake level (UL) for folate of 1 mg for adult men and women, and a UL of 800 µg for pregnant and lactating (breast-feeding) women less than 18 years of age. Supplemental folic acid should not exceed the UL to prevent folic acid from masking symptoms of vitamin B12 deficiency.[122]

Research suggests high levels of folic acid can interfere with some malaria|antimalarial treatments.[123]

A 10,000-patient study at Tufts University in 2007 concluded that excess folic acid worsens the effects of B12 deficiency and in fact may affect the absorption of B12.[124]

A study at the University of Adelaide concluded that the intake of folic acid supplements during late pregnancy increases the risk of babies developing childhood asthma by 30%, although researchers emphasized that their finding did not contradict recommendations to supplement folic acid in first trimester, when no additional risk was found.[125]

Elderly population

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There are benefits and risks of food folic acid fortification for elderly populations.[126] Elevated exposure to folic acid due to fortification can improve folate and homocysteine levels but can also mask symptoms of vitamin B12 deficiency.[126] A study where 747 subjects aged 67 to 96 years were measured for B vitamin and homocysteine status showed that diets with folic acid fortification of 140 µg/100 g of grain product decreased homocysteine level and heart disease risk.[126] However, Canada's food supply is fortified with 150 µg/100 g of grain and much of the elderly population also take a supplement which includes a folic acid component of 400 µg. Therefore it is important not to consume quantities over the recommended DRI.

Folate deficiency

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Folate deficiency may lead to glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube defects and brain defects (during pregnancy).[127] Folate deficiency is diagnosed by analyzing CBC and plasma vitamin B12 and folate levels.[127] CBC may indicate megaloblastic anemia but this could also be a sign of vitamin B12 deficiency.[127] A serum folate of 3 μg/L or lower indicates deficiency.[127] Serum folate level reflects folate status but erythrocyte folate level better reflects tissue stores after intake.[127] An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status.[127] Increased homocysteine level suggests tissue folate deficiency but homocysteine is also affected by vitamin B12 and vitamin B6, renal function, and genetics.[127] One way to differentiate between folate deficiency from vitamin B12 deficiency is by testing for methylmalonic acid levels.[127] Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B12 deficiency.[127] Folate deficiency is treated with supplemental oral folate of 400 to 1000 μg per day.[127] This treatment is very successful in replenishing tissues even if deficiency was caused by malabsorption.[127] Patients with megaloblastic anemia need to be tested for vitamin B12 deficiency before folate treatment because if the patient has vitamin B12 deficiency, folate supplementation can remove the anemia but can also worsen neurologic problems.[127] Morbidly obese patients with BMIs of greater than 50 are more likely to develop folate deficiency.[128] Patients with celiac disease have a higher chance of developing folate deficiency.[128] Cobalamin deficiency may lead to folate deficiency which in turn increases homocysteine levels and finally may result in the development of cardiovascular disease or birth defects.[129]

Iron-Folic acid supplementation risk for children

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Some studies show that iron-folic acid supplementation in children under 5 may result in increased mortality due to malaria; this has prompted the World Health Organization to alter their iron-folic acid supplementation policies for children in malaria prone areas such as India.[130]

Dietary fortification

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Image:GrainProducts.jpg|right|thumb|In the USA many grain products are fortified with folic acid.

See also: Food fortification

Since the discovery of the link between insufficient folic acid and neural tube defects (NTDs), governments and health organizations worldwide have made recommendations concerning folic acid dietary supplement|supplementation for women intending to become Pregnancy|pregnant.

This has led to the introduction in many countries of fortification, where folic acid is added to flour with the intention of everyone benefiting from the associated rise in blood folate levels. This is controversial, with issues having been raised concerning individual liberty [citation needed], and the masking effect of folate fortification on pernicious anaemia (vitamin B12 deficiency). However, several western countries now fortify their flour, along with a number of Middle Eastern countries and Indonesia. Mongolia and a number of Soviet Union|ex-Soviet republics are amongst those having widespread voluntary fortification; about five more countries (including Morocco, the first African country) have agreed but not yet implemented fortification. To date, no European Union|EU country has yet mandated fortification.[131]

Folates can be produced by engineering Lactococcus lactis strains using a rodent depletion-repletion bioassay and the bioavailabilities of these folates are comparable with commercial folic acid currently being used for food fortification.[132] These engineered folates can potentially help alleviate the effects of folate deficiency in the diet.[133] Hematologic studies show an improvement in megaloblastic anemia after the addition of L. lactis strains; this again suggests that lactic acid bacteria can potentially reverse some of the harm done by folate deficiency by acting as an essential, bioavailable vitamin.[134]

Effects of fortification and plasma folate and homocysteine levels

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A study has shown that folate fortification will substantially increase in folate status, particularly for the elderly. In the study group, the subjects who did not use vitamin supplements has increased folate concentrations of 4.6 ng/mL to 10.0 ng/mL (11 to 23 nmol/L) (P<0.001) from the base-line visit to the follow-up visit. The prevalence of low folate concentrations (<3 ng/mL [7 nmol/L]) decreased from 22.0% to 1.7% (P< 0.001). The mean total homocysteine concentration has decreased from a value of 10.1 µmol/L to 9.4 µmol/L during this period (P<0.001), while the prevalence of high homocysteine concentrations (>13 µmol/L) has been reduced from 18.7% to 9.8% (P<0.001). To further clarify the study methods, there were no statistically significant changes in concentrations of folate or homocysteine for the control group.[135]

Australia

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There has been previous debate in Australia regarding the inclusion of folic acid in products such as bread and flour.[136]

Australia and New Zealand have jointly agreed to fortification though the Food Standards Australia New Zealand. Australia will fortify all flour from 18 September 2009.[137] Although the food standard covers both Australia and New Zealand, an Australian government official has stated it is up to New Zealand to decide whether to implement it in New Zealand, and they will watch with interest.[138].

The requirement is 0.135 mg of folate per 100g of bread.

Canada

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In 2003, a Hospital for Sick Children, University of Toronto, research group published findings showing that the fortification of flour with folic acid in Canada has resulted in a dramatic decrease in neuroblastoma, an early and very dangerous cancer in young children.[139] In 2009, further evidence from McGill University showed a 6.2% decrease per year in the birth prevalence of severe congenital heart defects.[140]

Folic acid used in fortified foods is a synthetic form called pteroylmonoglutamate.[141] It is in its oxidized state and contains only one conjugated glutamate residue.[141] Folic acid therefore enters via a different carrier system than naturally occurring folate and this may have different effects on folate binding proteins and its transporters.[142] Folic acid has a higher bioavailability than natural folates and are rapidly absorbed across the intestine[141], therefore it is important to consider the Dietary Folate Equivalent (DFE) when calculating your intake. Natural occurring folate is equal to 1 DFE, however 0.6 µg of folic acid is equal to 1 DFE.

Folic acid food fortification became mandatory in Canada in 1998, with the fortification of 150 µg of folic acid per 100 grams of enriched flour and uncooked cereal grains.[143] The purpose of fortification was to decrease the risk of neural tube defects in newborns.[143] It is important to fortify grains because it is a widely eaten food and the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant. Canada's fortification program has been successful with a decrease of neural tube defects by 19% since its introduction.[144] A 7 province study from 1993 to 2002 showed a reduction of 46% in the overall rate of neural tube defects after folic acid fortification was introduced in Canada.[145] The fortification program was estimated to raise a person’s folic acid intake level by 70–130 µg/day, however an increase of almost double that amount was actually observed.[144] This could be from the fact that many foods are over fortified by 160–175% the predicted value.[144] In addition, much of the elder population take supplements which adds 400 µg to their daily folic acid intake. This is a concern because 70-80% of the population have detectable levels of unmetabolized folic acid in their blood and high intakes can accelerate the growth of preneoplasmic lesions.[146] It is still unknown the amount of folic acid supplementation that might cause harm,[143]. However, if Canada is going to continue fortifying the food supply they may want to consider decreasing the amount in foods and supplements from 400 µg to 100 or 50 µg.[146]

Folic acid supplementation promotion in Canada

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According to a Canadian survey, 58% of women said they took a folic acid containing multivitamin or a folic acid supplement as early as three months before becoming pregnant.[145] Women in higher income households and with more years of school education are using more folic acid supplements before pregnancy.[145] Women with planned pregnancies and who are over the age of 25 are more likely to use folic acid supplements.[145] Canadian public health efforts are focused on promoting awareness of the importance of folic acid supplementation for all women of childbearing age and decreasing socio-economic inequalities by providing practical folic acid support to vulnerable groups of women.[145]

New Zealand

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New Zealand was going to fortify bread (excluding organic and unleavened varieties) from 18 September 2009 but has opted to wait until more research is done.[137]

The Association of Bakers [147] and the Green Party of Aotearoa New Zealand|Green Party [148] have opposed mandatory fortification, describing it as "mass medication". Food Safety Minister Kate Wilkinson (politician)|Kate Wilkinson reviewed the decision to fortify in July 2009, citing links between overconsumption of folate with cancer [149]. The New Zealand Government is reviewing whether it will continue with the mandatory introduction of folic acid to bread.[150]

United Kingdom

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There has been previous debate in the United Kingdom regarding the inclusion of folic acid in products such as bread and flour.[151]

The Food Standards Agency has recommended fortification.[152][153][154]

United States

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The United States Public Health Service recommends an extra 0.4 mg/day, which can be taken as a pill. However, many researchers believe that supplementation in this way can never work effectively enough since about half of all pregnancies in the U.S. are unplanned and not all women will comply with the recommendation. Approximately 53% of the US population uses dietary supplements and 35% uses dietary supplements containing folic acid.[155] Men consume more folate (in dietary folate equivalents) than women and non-Hispanic whites have higher folate intakes than Mexican Americans and non-Hispanic blacks.[155] Twenty nine percent of black women have inadequate intakes of folate.[155] The age group consuming the most folate and folic acid is the >50 group.[155] Only 5% of the population exceeds the Tolerable Upper Intake Level.[155]

In 1996, the United States Food and Drug Administration (FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products.[156][157] This ruling took effect on January 1, 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.[158] There are concerns that the amount of folate added is insufficient [159]. In October 2006, the Australian press claimed that U.S. regulations requiring fortification of grain products were being interpreted as disallowing fortification in non-grain products, specifically Vegemite (an Australian yeast extract containing folate). The FDA later said the report was inaccurate, and no ban or other action was being taken against Vegemite.[160]

As a result of the folic acid fortification program, fortified foods have become a major source of folic acid in the American diet. The Centers for Disease Control and Prevention in Atlanta, Georgia used data from 23 birth defect registries that cover about half of United States births, and extrapolated their findings to the rest of the country. These data indicate that since the addition of folic acid in grain-based foods as mandated by the FDA, the rate of neural tube defects dropped by 25% in the United States[161]. The results of folic acid fortification on the rate of neural tube defects in Canada have also been positive, showing a 46% reduction in prevalence of NTDs;[162] the magnitude of reduction was proportional to the prefortification rate of NTDs, essentially removing geographical variations in rates of NTDs seen in Canada before fortification.

When the U.S. Food and Drug Administration set the folic acid fortification regulation in 1996, the projected increase in folic acid intake was 100 µg/d.[163] Data from a study with 1480 subjects showed that folic acid intake increased by 190 µg/d and total folate intake increased by 323 µg dietary folate equivalents (DFE)/d.[163] Folic acid intake above the upper tolerable intake level (1000 µg folic acid/d) increased only among those individuals consuming folic acid supplements as well as folic acid found in fortified grain products.[163] Taken together, folic acid fortification has led to a bigger increase in folic acid intake than first projected.[163]

Future directions for research

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  • Identifying polymorphisms or mutations in genes involved in the synthesis of thymidylate, purines, regulatory proteins, or substrates involved in folate and homocysteine metabolism, such as serine hydroxymethyltransferase and methylenetetrahydrofolate dehydrogenase, rather than simply focusing on 5,10-methylenetetrahydrofolate reductase as the main cause [164].
  • Direct/ Indirect look at the adverse effects of our greatly increased folic acid intakes
  • Human studies looking into whether folate will interfere with the effectiveness of antifolate treatments and the possibility that it may support cancer growth[165]
  • More epidemiologic and clinical studies are need to be done on human tumor sample to fully understand the role of folate receptor alpha in tumor etiology, progression, and patient survival.[166]

See also

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  • Dietary supplement

References

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  1. ↑ Ural, Serdar H. (2008-11). "Folic Acid and Pregnancy". Kid's Health. {{cite web}}: Check date values in: |date= (help)
  2. ↑ a b c d Bailey SW, Ayling JE (2009). "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake". Proceedings of the National Academy of Sciences of the United States of America. 106 (36): 15424–9. doi:10.1073/pnas.0902072106. PMC 2730961. PMID 19706381. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ↑ a b c d Weinstein SJ et al Null Association Between Prostate Cancer and Serum Folate, Vitamin B6, Vitamin B12, and Homocysteine Vol 12 pg 1271-1272 Cancer Epidemiology, Biomarkers, & Prevention November 2003
  4. ↑ "Dietary Supplement Fact Sheet: Folate". Office of Dietary Supplements, National Institutes of Health.
  5. ↑ a b Ebbing M, Bønaa KH, Nygård O; et al. (2009). "Cancer incidence and mortality after treatment with folic acid and vitamin B12". JAMA. 302 (19): 2119–26. doi:10.1001/jama.2009.1622. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  6. ↑ New York Times World's Healthiest Foods
  7. ↑ a b c Barr, S. FNH 371:Human Nutrition Over the Life Span, course notes. (2009), page 19
  8. ↑ a b c http://www.eatrightontario.ca/en/ViewDocument.aspx?id=109
  9. ↑ [1]
  10. ↑ "Reports by Single Nutrients". USDA. 2009-02-13. Retrieved 2009-03-19. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  11. ↑ Dietrich M, Brown CJ & Block G (2005) The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr 24, 266-274.
  12. ↑ Suitor CW & Bailey LB (2000) Dietary folate equivalents: interpretation and application. J Am Diet Assoc 100, 88-94.
  13. ↑ a b [2]
  14. ↑ Cabanillas M, Moya Chimenti E, González Candela C, Loria Kohen V, Dassen C, Lajo T. Nutr Hosp. 2009 Sep-Oct;24(5):535-42. Usefulness of meal replacement: analysis of the principal meal replacement products commercialised in Spain
  15. ↑ a b c d Lanska DJ. Handb Clin Neurol. 2009;95:445-76. Chapter 30 Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins.
  16. ↑ Mitchell HK, Snell EE, Williams RJ (1941). "The concentration of "folic acid"". J Am Chem Soc. 63 (8): 2284. doi:10.1021/ja01853a512.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ↑ a b Hoffbrand AV & Weir DG (2001) The history of folic acid. Br J Haematol 113, 579-589.
  18. ↑ Angier RB, Boothe JH, Hutchings BL, Mowat JH, Semb J, Stokstad EL, Subbarow Y, Waller CW, Cosulich DB, Fahrenbach MJ, Hultquist ME, Kuh E, Northey EH, Seeger DR, Sickels JP & Smith JM, Jr.helped the process of research(1945) Synthesis of a Compound Identical with the L. Casei Factor Isolated from Liver. Science 102, 227-228.
  19. ↑ a b Kamen B (1997). "Folate and antifolate pharmacology". Seminars in oncology. 24 (5 Suppl 18): S18–30–9. PMID 9420019.
  20. ↑ figueiredo et al 2009 Folic Acid and Risk or Prostate Cancer: Results From a Randomized Clinical Trial
  21. ↑ Smith C, Lieberman M, Marks DB, Marks AD (2007). Marks' essential medical biochemistry. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-9340-8.{{cite book}}: CS1 maint: multiple names: authors list (link)
  22. ↑ Zittoun J (1993). "Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism". La Revue du praticien. 43 (11): 1358–63. PMID 8235383. Template:Fr icon
  23. ↑ http://www.healthlinkbc.ca/healthfiles/hfile68g.stm
  24. ↑ Goh YI & Koren G (2008) Folic acid in pregnancy and fetal outcomes. J Obstet Gynaecol 28, 3-13.
  25. ↑ EC 1.5.1.3
  26. ↑ Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL (1994). "Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91". Advance Data (258): 1–28. PMID 10138938.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ↑ Raiten DJ, Fisher KD (1995). "Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994)". The Journal of Nutrition. 125 (5): 1371S–1398S. PMID 7738698.
  28. ↑ Lewis CJ, Crane NT, Wilson DB, Yetley EA (1999). "Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use". The American Journal of Clinical Nutrition. 70 (2): 198–207. PMID 10426695.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ↑ Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA (1995). "Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects". Epidemiology. 6 (3): 219–226. doi:10.1097/00001648-199505000-00005. PMID 7619926.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ↑ Mulinare J, Cordero JF, Erickson JD, Berry RJ (1988). "Periconceptional use of multivitamins and the occurrence of neural tube defects". Journal of the American Medical Association. 260 (21): 3141–3145. doi:10.1001/jama.260.21.3141. PMID 3184392.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ↑ Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, Willett W (1989). "Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects". Journal of the American Medical Association. 262 (20): 2847–2852. doi:10.1001/jama.262.20.2847. PMID 2478730.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ↑ Folic acid supplements and risk of facial clefts: national population based case-control study. Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, Vindenes H, Vollset SE, Drevon CA. BMJ. 2007 Mar 3;334(7591):464. Epub 2007 Jan 26. PMID: 17259187
  33. ↑ Goh YI & Koren G (2008) "Folic acid in pregnancy and fetal outcomes", J. Obstet. Gynaecol. 28:3–13.
  34. ↑ Wilton DC, Foureur MJ. Women Birth. 2009 Oct 12. A survey of folic acid use in primigravid women.
  35. ↑ Health Professionals Recommendations, Folic Acid, NCBDDD, CDC
  36. ↑ [3]
  37. ↑ a b Steegers-Theunissen RP et al., PLoS One. 2009 Nov 16;4(11):e7845. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child.
  38. ↑ a b Folic acid: influence on the outcome of pregnancy, Scholl TO et al, American Journal of Clinical Nutrition, Vol. 71, No. 5, 1295S-1303s, May 2000
  39. ↑ Milne E et al., Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring. Int J Cancer. 2009 Oct 16.
  40. ↑ a b Medical News: Extra Folate for Men May Reduce Birth Defects - in Primary Care, Diet & Nutrition from MedPage Today; citing S.S. Young et al., The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men. Human Reproduction pp. 1–9, 2008
  41. ↑ McGuire M, Cleary B, Sahm L, Murphy DJ. Hum Reprod. 2009 Nov 12. Prevalence and predictors of periconceptional folic acid uptake--prospective cohort study in an Irish urban obstetric population.
  42. ↑ Jia ZL, Li Y, Chen CH, Li S, Wang Y, Zheng Q, Shi B. DNA Cell Biol. 2009 Nov 6. Association Among Polymorphisms at MYH9, Environmental Factors, and Nonsyndromic Orofacial Clefts in Western China.
  43. ↑ http://www.extension.iastate.edu/Publications/N3401.pdf
  44. ↑ Refsum H, Ueland PM, Nygard O, Vollset SE (1998). "Homocysteine and cardiovascular disease". Annual Review of Medicine. 49 (1): 31–62. doi:10.1146/annurev.med.49.1.31. PMID 9509248.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  45. ↑ Malinow MR (1995). "Plasma homocyst(e)ine and arterial occlusive diseases: A mini-review". Clinical Chemistry. 41 (1): 173–6. PMID 7813076.
  46. ↑ NORVIT Trial- High dose B vitamins do not lower stroke or MI risk
  47. ↑ Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ (2006). "Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial". J Am Coll Cardiol. 47 (6): 1108–16. doi:10.1016/j.jacc.2005.10.064. PMID 16545638.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  48. ↑ Lonn, E; Yusuf, S; Arnold, MJ; Sheridan, P; Pogue, J; Micks, M; McQueen, MJ; Probstfield, J; Fodor, G (2006). "Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease". N Engl J Med. 354 (15): 1567–77. doi:10.1056/NEJMoa060900. PMID [http://content.nejm.org/cgi/reprint/NEJMoa060900v1.pdf Full text PDF 16531613 [http://content.nejm.org/cgi/reprint/NEJMoa060900v1.pdf Full text PDF]]. {{cite journal}}: Check |pmid= value (help); External link in |pmid= (help)
  49. ↑ Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K (2006). "Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction". N Engl J Med. 354 (15): 1578. doi:10.1056/NEJMoa055227. PMID [http://content.nejm.org/cgi/reprint/NEJMoa055227v1.pdf Full text PDF 16531614 [http://content.nejm.org/cgi/reprint/NEJMoa055227v1.pdf Full text PDF]]. {{cite journal}}: Check |pmid= value (help); External link in |pmid= (help)CS1 maint: multiple names: authors list (link)
  50. ↑ Williams C, Kingwell BA, Burke K, McPherson J, Dart AM (1 July 2005). "Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype". Am J Clin Nutr. 82 (1): 26–31. PMID 16002796.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  51. ↑ Brief, high doses of folate blunt damage from heart attack
  52. ↑ Papandreou D et al Int J Food Sci Nutr. 2009 Nov 26.Homocysteine lowering with folic acid supplements in children: Effects on blood pressure.
  53. ↑ Palomba S, Falbo A, Giallauria F, Russo T, Tolino A, Zullo F, Colao A, Orio F. Diabetes Care. 2009 Nov 23. Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome.
  54. ↑ Bazzano LA. Am J Med Sci. 2009 Jul;338(1):48-9. Folic acid supplementation and cardiovascular disease: the state of the art.
  55. ↑ Stewart CP, Christian P, Schulze KJ, Leclerq SC, West KP Jr, Khatry SK. J Nutr. 2009 Aug;139(8):1575-81. Epub 2009 Jun 23. Antenatal micronutrient supplementation reduces metabolic syndrome in 6- to 8-year-old children in rural Nepal.
  56. ↑ Imasa MS, Gomez NT, Nevado JB Jr. Asian Cardiovasc Thorac Ann. 2009 Jan;17(1):13-21. Folic acid-based intervention in non-ST elevation acute coronary syndromes.
  57. ↑ BBC Folic acid 'reduces stroke risks' 31 May 2007
  58. ↑ Terwecoren A, Steen E, Benoit D, Boon P, Hemelsoet D. Acta Neurol Belg. 2009 Sep;109(3):181-8. Ischemic stroke and hyperhomocysteinemia: truth or myth?
  59. ↑ Duthie SJ, Folic acid deficiency and cancer: mechanisms of DNA instability, British Medical Bulletin 55:578-592 (1999)
  60. ↑ Van Guelpen B (2007). "Folate in colorectal cancer, prostate cancer and cardiovascular disease". Scand J Clin Lab Invest. 67 (5): 459–73. doi:10.1080/00365510601161513. PMID 17763182.
  61. ↑ Jennings E (1995). "Folic acid as a cancer-preventing agent". Med Hypotheses. 45 (3): 297–303. doi:10.1016/0306-9877(95)90121-3. PMID 8569555.
  62. ↑ Kim YI (1 November 2004). "Will mandatory folic acid fortification prevent or promote cancer?". Am J Clin Nutr. 80 (5): 1123–8. PMID 15531657.
  63. ↑ a b Ulrich American Journal of Clinical Nutrition, Vol. 86, No. 2, 271-273, August 2007 Folate and cancer prevention: a closer look at a complex picture
  64. ↑ Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ (2005). "Folate intake and colorectal cancer risk: a meta-analytical approach". Int J Cancer. 113 (5): 825–8. doi:10.1002/ijc.20648. PMID 15499620.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  65. ↑ Giovannucci E, Stampfer MJ, Colditz GA; et al. (1998). "Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study". Ann. Intern. Med. 129 (7): 517–24. PMID 9758570. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  66. ↑ Cole BF, Baron JA, Sandler RS; et al. (2007). "Folic acid for the prevention of colorectal adenomas: a randomized clinical trial". JAMA. 297 (21): 2351–9. doi:10.1001/jama.297.21.2351. PMID 17551129. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  67. ↑ Johansson M et al Feb 2008 17(2) Cancer Epidemiol Biomarkers Prev, Circulating Concentrations of Folate and Vitamin B12 in Relation to Prostate Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study
  68. ↑ Johansson M et al Feb 2008 17(2) Cancer Epidemiol Biomarkers Prev, Circulating Concentrations of Folate and Vitamin B12 in Relation to Prostate Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study
  69. ↑ Larsson SC, Håkansson N, Giovannucci E, Wolk A (2006). "Folate intake and pancreatic cancer incidence: a prospective study of Swedish women and men". J Natl Cancer Inst. 98 (6): 407–13. doi:10.1093/jnci/djj094. PMID 16537833.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  70. ↑ Kim YI (2006). "Does a high folate intake increase the risk of breast cancer?". Nutr Rev. 64 (10 Pt 1): 468–75. doi:10.1301/nr.2006.oct.468-475. PMID 17063929.
  71. ↑ Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfält E (2007). "High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmö Diet and Cancer cohort". Am J Clin Nutr. 86 (2): 434–43. PMID 17684216.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  72. ↑ Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, JoAnn E. Manson (2008). "Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial". JAMA. 300 (17): 2012–21. doi:10.1001/jama.2008.555. PMC 2593624. PMID 18984888. {{cite journal}}: Text "Manson JE" ignored (help)CS1 maint: multiple names: authors list (link)
  73. ↑ a b Zhang S et al, Vol. 281 No. 17, May 5, 1999, 1632-1637, JAMA, A Prospective Study of Folate Intake and the Risk of Breast Cancer
  74. ↑ "MedlinePlus: Folic Acid Supplements Raise Prostate Cancer Risk".
  75. ↑ figueiredo et al 2009 folic acid and risk of prostate cancer: results form a randomized clinical trial
  76. ↑ figueiredo et al 2009 folic acid and risk of prostate cancer: results form a randomized clinical trial
  77. ↑ figueiredo et al 2009 folic acid and risk of prostate cancer: results form a randomized clinical trial
  78. ↑ figueiredo et al 2009 folic acid and risk of prostate cancer: results form a randomized clinical trial
  79. ↑ "folic-acid and Xeloda Interactions"
  80. ↑ a b c [4]
  81. ↑ a b Hazra A, Selhub J, Chao WH, Ueland PM, Hunter DJ, Baron JA. Am J Clin Nutr. 2009 Nov 18. Uracil misincorporation into DNA and folic acid supplementation.
  82. ↑ a b Seto SW, Lam TY, Or PM, Lee WY, Au AL, Poon CC, Li RW, Chan SW, Yeung JH, Leung GP, Lee SM, Ngai SM, Kwan YW. J Nutr Biochem. 2009 Oct 30. Folic acid consumption reduces resistin level and restores blunted acetylcholine-induced aortic relaxation in obese/diabetic mice.
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  87. ↑ Shiroky JB (1997). "The use of folates concomitantly with low-dose pulse methotrexate". Rheumatic Diseases Clinics of North America. 23 (4): 969–80. doi:10.1016/S0889-857X(05)70369-0. PMID 9361164.
  88. ↑ Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". Mutation Research. 397 (2): 221–8. PMID 9541646.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  89. ↑ Morgan SL, Baggott JE Template:Section:Chapter reference after author
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  94. ↑ Delgado-Villa MJ, Ojeda ML, Rubio JM, Murillo ML, Sánchez OC. J Stud Alcohol Drugs. 2009 Jul;70(4):615-22. Beneficial role of dietary folic acid on cholesterol and bile acid metabolism in ethanol-fed rats.
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  101. ↑ Durga J, van Boxtel MP, Schouten EG; et al. (2007). "Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial". Lancet. 369 (9557): 208–16. doi:10.1016/S0140-6736(07)60109-3. PMID 17240287. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  103. ↑ Krebs MO, Bellon A, Mainguy G, Jay TM, Frieling H. Trends Mol Med. 2009 Nov 5. One-carbon metabolism and schizophrenia: current challenges and future directions.
  104. ↑ Matsui EC, Matsui WM The Journal of Allergy and Clinical Immunology Vol 123 Issue 6 Pg1253-1259 June 2009 High Serum Folate Levels are Associated with a Lower Risk of Atopy and Wheeze
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  112. ↑ Christen WG, Glynn RJ, Chew EY, Albert CM, JoAnn E. Manson (2009). "Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study". Arch Intern Med. 169 (4): 335–41. doi:10.1001/archinternmed.2008.574. PMC 2648137. PMID 19237716. {{cite journal}}: Text "Manson JE" ignored (help)CS1 maint: multiple names: authors list (link)
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  122. ↑ Baggott JE, Morgan SL, HaT, Vaughn WH, Hine RJ (1992). "Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs". Biochemical Journal. 282 (Pt 1): 197–202. PMC 1130907. PMID 1540135.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  124. ↑ Foodproductiondaily
  125. ↑ Popular Science Uh-oh: Folic Acid Linked to Rise in Childhood Asthma 4 November 2009
  126. ↑ a b c Folic Acid Fortification of the Food Supply: Potential Benefits and Risks for the Elderly Population, Tucker KL et al, JAMA, 1996;276(23):1879-1885.
  127. ↑ a b c d e f g h i j k l http://www.merck.com
  128. ↑ a b Malterre T (2009). "Digestive and nutritional considerations in celiac disease: could supplementation help?" (PDF). Alternative Medicine Review. 14 (3): 247–57. PMID 19803549. {{cite journal}}: Unknown parameter |month= ignored (help)Template:MEDRS
  129. ↑ Varela-Moreiras G, Murphy MM, Scott JM (2009). "Cobalamin, folic acid, and homocysteine". Nutrition Reviews. 67 (Suppl 1): S69–72. doi:10.1111/j.1753-4887.2009.00163.x. PMID 19453682. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  130. ↑ Pasricha S, Shet A, Sachdev HP, Shet AS (2009). "Risks of routine iron and folic acid supplementation for young children" (PDF). Indian Pediatrics. 46 (10): 857–66. PMID 19887691. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  131. ↑ Russell A (2006). "The UK campaign on folic acid and flour fortification". Cerebrospinal Fluid Res. 3 (Suppl 1): S33. doi:10.1186/1743-8454-3-S1-S33. PMC 1716791.
  132. ↑ Leblanc JG et al, Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats. Nutrition. 2009 Nov 18.
  133. ↑ Leblanc JG et al, Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats. Nutrition. 2009 Nov 18.
  134. ↑ Leblanc JG, Sybesma W, Starrenburg M; et al. (2009). "Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats". Nutrition. doi:10.1016/j.nut.2009.06.023. PMID 19931414. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  135. ↑ Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH (1999). "The effect of folic acid fortification on plasma folate and total homocysteine concentrations". The New England Journal of Medicine. 340 (19): 1449–54. doi:10.1056/NEJM199905133401901. PMID 10320382. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  136. ↑ "Bread fortification 'not justified'". The Sydney Morning Herald. 29 July 2006. http://www.smh.com.au/news/National/Bread-fortification-not-justified/2006/07/29/1153816426688.html. 
  137. ↑ a b "Bread to be fortified with folic acid". NZ Herald. 2007-06-22. http://www.nzherald.co.nz/topic/story.cfm?c_id=294&objectid=10447345. Retrieved 2009-07-13. 
  138. ↑ "Bread additive call 'up to NZ'". http://www.stuff.co.nz/national/politics/2593949/Bread-additive-call-up-to-NZ. Retrieved 2009-07-15. 
  139. ↑ French AE, Grant R, Weitzman S, Ray JG, Vermeulen MJ, Sung L, Greenberg M, Gideon Koren|Koren G. Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharmacol Ther 2003; 74: 288-94.
  140. ↑ Ionescu-Ittu, R.; Marelli, A. J; MacKie, A. S; Pilote, L. (2009). "Prevelance of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada". Brit Med J. 338 (7705): 1261. doi:10.1136/bmj.b1673. {{cite journal}}: Unknown parameter |ionescu= ignored (help)
  141. ↑ a b c Smith, A. D., Kim, Y. I., & Refsum, H. (2008). "Is folic acid good for everyone? American Journal of Clinical Nutrition". 3 (87): 517. {{cite journal}}: Cite journal requires |journal= (help)CS1 maint: multiple names: authors list (link)
  142. ↑ Ulrich C.M. and Potter, J.D. (2006). "Folate supplementation: Too much of a good thing?". Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 15 (2): 189–93. doi:10.1158/1055-9965.EPI-06-0054. PMID 16492904. Retrieved 11/12/2009. {{cite journal}}: Check date values in: |accessdate= (help); Unknown parameter |doi_brokendate= ignored (|doi-broken-date= suggested) (help)
  143. ↑ a b c Mason J. B., Dickstein, A., Jacques, P. F., Haggarty, P., Selhub, J., Dallal, G.; et al. (2007). "A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: A hypothesis. Cancer Epidemiology Biomarkers & Prevention". 7 (16): 1325. {{cite journal}}: Cite journal requires |journal= (help); Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  144. ↑ a b c Quinlivan, E. P., & Gregory III, J. F. (2003). "Effect of food fortification on folic acid intake in the united states". American Journal of Clinical Nutrition. 1 (77): 221.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  145. ↑ a b c d e http://www.hc-sc.gc.ca
  146. ↑ a b "Folic-acid fortification of flour and increased rates of colon cancer". 2009 Retrieved 11/09, 2009. {{cite journal}}: Cite journal requires |journal= (help); Check date values in: |year= (help); Unknown parameter |name= ignored (help)
  147. ↑ Association Of Bakers (2009-07-08). "Work Starts on Wilkinson’s Mass Medication Plan". Press release. http://www.scoop.co.nz/stories/BU0907/S00210.htm. Retrieved 2009-07-13. 
  148. ↑ Green Party (2009-07-09). "NZ should push pause on folic fortification". Press release. http://www.scoop.co.nz/stories/PA0907/S00132.htm. Retrieved 2009-07-13. 
  149. ↑ "Bakers, Govt battle over folic acid". NZ Herald. 2009-07-08. http://www.nzherald.co.nz/food/news/article.cfm?c_id=206&objectid=10583249. Retrieved 2009-07-13. 
  150. ↑ "Govt reviewing folic acid policy". Stuff. http://www.stuff.co.nz/national/politics/2593407/Govt-reviewing-folic-acid-policy. Retrieved 15 July 2009. 
  151. ↑ BBC 'Put folic acid in bread' 2000-01-13
  152. ↑ FSA (2007-05-17). "Board recommends mandatory fortification". Retrieved 2007-05-18.
  153. ↑ "Backing for folic acid in bread". BBC News. 17 May 2007. http://news.bbc.co.uk/1/hi/health/6665109.stm. Retrieved 2007-05-18. 
  154. ↑ BBC Experts back folic acid in flour 11 May 2007
  155. ↑ a b c d e Bailey RL et al Am J Clin Nutr. 2009 Nov 18. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006.
  156. ↑ Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD, Phillipson BE, Gluckman RA, Block PC, Upson BM (1998). "Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease". New England Journal of Medicine. 338 (15): 1009–15. doi:10.1056/NEJM199804093381501. PMID 9535664.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  157. ↑ Daly S, Mills JL, Molloy AM, Conley M, Lee YJ, Kirke PN, Weir DG, Scott JM (1997). "Minimum effective dose of folic acid for food fortification to prevent neural-tube defects". Lancet. 350 (9092): 1666–9. doi:10.1016/S0140-6736(97)07247-4. PMID 9400511.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  161. ↑ Centers for Disease Control and Prevention (CDC) (2004). "Spina bifida and anencephaly before and after folic acid mandate--United States, 1995-1996 and 1999-2000". Morbidity and Mortality Weekly Report. 53 (17): 362–5. PMID 15129193.
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Bibliography

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Biochemistry links
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