Several epidemiological studies also provide evidence that an elevated total plasma level

of Homocysteine (tHcy) is associated with an increased risk of psychiatric disorders such as

depression [45-48]. Most of these studies suggest that a significant association is observed for

tHcy levels above 12-15 μmol/L [45, 46]. For instance, the Hordaland Homocysteine Study

(HHS-II) has shown that subjects with tHcy > 15umol/L had a two-fold higher risk of having

depression compared with those with tHcy < 9 umol/L. In addition, it was observed that those

with Methyltetrahydrofolate Reductase (MTHFR) 677 TT genotype had a 70% higher risk of

depression compared with the CC genotype [45-48]. This effect is exacerbated in the

presence of low folate status, indicating a strong gene-nutrient interaction [45]. These data

may suggest that some depressed patients are genetically vulnerable and that they may

benefit from folic acid supplementation in addition to their antidepressant treatment. There is

some limited evidence from randomised controlled trials that using folic acid in addition to

antidepressant medication may have benefits [49]. However, the evidence is probably too

limited at present for this to be a routine treatment recommendation. To date, the association

between tHcy, depression score and risk of depression needs to be fully evaluated.

FOLIC ACID AND CANCER

Several studies have recently implicated folate in modulating the risk of several cancers

[3], in particular, colorectal and breast cancer [50]. Folate is involved in the synthesis, repair,

and functioning of DNA and a deficiency of folate may result in damage to DNA that may

lead to cancer [51]. It is not clear whether folate itself has a direct link to the risk of cancer of

various sites, as other dietary factors (e.g. alcohol, methionine) as well as genetic

polymorphisms seem to modulate the risk. Polymorphism of a potentially wide range of other

enzymes involved in folate metabolism may also modulate the risk of cancer [50].

Although folate could prevent cancer in healthy people, it might also promote the

progression of pre-malignant and malignant lesions. Low folate status and antifolate

treatment, respectively, inhibit human tumor growth in these stages [52-56]. The results of

studies in animals suggest that the effect of folate on carcinogenesis is dependent on the stage

of the carcinogenic process and the dose of folate tested [56]; folate deficiency inhibits,

whereas folate supplementation promotes the progression of established tumors.

Concerning the association between folate and colon cancer, data from prospective

studies [57,58] and case-control studies [59-62], indicate that inadequate intake of folate may

increase the risk of this type of cancer.

Folic Acid and Health: An Overview 47

Recent epidemiological studies also support an inverse association between folate status

and the rate of colorectal adenomas and carcinomas. High dietary folate (including

supplements), but not folate from foods only, was inversely associated with the risk of

colorectal adenoma in women (RR= 0.66; 95% CI, 0.46-0.95) of the Nurses’ Health Study

[63], and in men (RR= 0.63; 95% CI, 0.41-0.98) of the Health Professional Follow-up Study

[64]. The relative risk of those with a high alcohol and low methionine and folate intake

compared with those with low alcohol and high folate and methionine consumption was 3.17

(95% CI, 1.69-5.95) (men and women combined). These findings suggest that maintaining

adequate folate levels may be important in reducing the risk of colon cancer. Animal trials

have also provided considerable support for the epidemiological findings [65], suggesting

that folate supplementation might decrease or increase cancer risk depending on timing and

dosage. Moreover, a recent cross-sectional study [66] has shown that high folate status in

smokers may confer increased or decreased risk for high risk adenoma, depending on the

MTHFR genotype.

Although not uniformly consistent, epidemiologic data also report an inverse association

between dietary intake and blood measurements of folate and the risk of breast cancer [67].

The risk of postmenopausal breast cancer may be increased among women with low intakes

of folate, especially those consuming alcohol-containing beverages [68]. Achieving adequate

circulating levels of folate may be particularly important in attenuating the risk of

postmenopausal breast cancer associated with family history, but only if alcohol use is

avoided or minimized [69]. More recent findings confirm the positive associations between

moderate alcohol consumption and breast cancer. However, they also suggest that a high

intake, generally attributable to supplemental folic acid, may increase the risk in

postmenopausal women. In particular, the Prostate, Lung, Colorectal, and Ovarian (PLCO)

Cancer Screening trial [70] has recently reported for the first time a potentially harmful effect

of high folate intake on breast cancer risk. In this study, the risk of developing breast cancer

was significantly increased by 20% in women taking supplemental folic acid intake ≥ 400

μg/d compared with those with no supplemental intake. Furthermore, although food folate

intake was not significantly related to breast cancer risk, total folate intake, mainly from folic

acid supplementation, significantly increased breast cancer risk by 32%. The data from the

PLCO trial also support prior observations made in epidemiologic, clinical, and animal

studies [50] suggesting that folate possesses dual modulatory effects on the development and

progression of cancer, depending on the timing and dose of folate intervention. Based on the

lack of compelling supportive evidence, routine folic acid supplementation should not be

recommended as a chemopreventive measure against breast cancer at present.

Data concerning the relationship between folate and other types of cancer are sparse and

controversial. A recent population-based prospective study [71] of 81,922 cancer free

Swedish women and men, has suggested that increased inatake of folate from food sources,

but not from supplements, may be associated with a reduced risk of pancreatic cancer. In the

same study, 61,084 women, aged 38-76 years, were also assessed for ovarian cancer risk and

the results have suggested that a high dietary folate intake may play a role in reducing the risk

of ovarian cancer, especially among women who consume alcohol [72]. The effect of folate

on carcinogenesis in the cervix remains uncertain. Two trials have shown no significant

48 Rossana Salerno-Kennedy

effect of folic acid on the rates of cervical intraepithelial neoplasia regression or progression

[50].