Folate Abstracts 2

© 2012

Variations in folate pathway genes are associated with unexplained female infertility            (Altmae, Stavreus-Evers et al. 2009) Download

OBJECTIVE: To investigate associations between folate-metabolizing gene variations, folate status, and unexplained female infertility. DESIGN: An association study. SETTING: Hospital-based IVF unit and university-affiliated reproductive research laboratories. PATIENT(S): Seventy-one female patients with unexplained infertility. INTERVENTION(S): Blood samples for polymorphism genotyping and homocysteine, vitamin B12, and folate measurements. MAIN OUTCOME MEASURE(S): Allele and genotype frequencies of the following polymorphisms: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C/T, 1298A/C, and 1793G/A, folate receptor 1 (FOLR1) 1314G/A, 1816delC, 1841G/A, and 1928C/T, transcobalamin II (TCN2) 776C/G, cystathionase (CTH) 1208G/T and solute carrier family 19, member 1 (SLC19A1) 80G/A, and concentrations of plasma homocysteine, vitamin B12, and serum folate. RESULT(S): MTHFR genotypes 677CT and 1793GA, as well as 1793 allele A were significantly more frequent among controls than in patients. The common MTHFR wild-type haplotype (677, 1298, 1793) CAG was less prevalent, whereas the rare haplotype CCA was more frequent in the general population than among infertility patients. The frequency of SLC19A1 80G/A genotypes differed significantly between controls and patients and the A allele was more common in the general population than in infertile women. Plasma homocysteine concentrations were influenced by CTH 1208G/T polymorphism among infertile women. CONCLUSION(S): Polymorphisms in folate pathway genes could be one reason for fertility complications in some women with unexplained infertility.

Serum folate and cancer mortality among U.S. adults: findings from the Third National Health and Nutritional Examination Survey linked mortality file

            (Yang, Bostick et al. 2009) Download

BACKGROUND: The relation between folate status and cancer is controversial. Several epidemiologic studies have suggested that increased folate intake is associated with reduced risk of various cancers, others have found no such associations, and a few have suggested that high folate intake might increase the risk of certain cancers. METHODS: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) Mortality File, a prospective cohort study of a nationally representative sample of 14,611 U.S. adults, we conducted Cox proportional hazards regression modeling to investigate the association of baseline serum folate concentrations and all-cancer mortality determined from linked death certificate data. RESULTS: Relative to the lowest quintile of serum folate (<3.0 ng/mL), the multivariable-adjusted hazard ratios across quintiles 2 to 5 were: 1.61 [95% confidence interval (95% CI), 1.11-2.32], 1.00 (95% CI, 0.65-1.49), 1.39 (95% CI, 0.96-2.03), and 0.85 (95% CI, 0.59-1.22). These findings did not differ substantially by age or sex, but the higher risk for those in the second quintile appeared limited to non-Hispanic whites. CONCLUSION: These findings suggest that there may be a nonlinear relationship between folate status and the risk of all-cancer mortality such that persons with low, but not grossly deficient, serum blood folate concentrations may be at increased risk. Further study is needed to determine whether these findings are due to chance, and if not, to clarify their biological basis.

Meta-analysis: folic acid in the prevention of colorectal adenomas and the chemoprevention of colorectal cancer

            (Carroll, Cooper et al. 2010) Download

Summary: Background: Folic acid has been identified as a possible agent for the chemoprevention of colorectal cancer. Aim: To assess the effectiveness of folic acid in reducing the recurrence of adenomas (precursors of colorectal cancer) among populations with a history of adenomas, and incidence of colorectal cancer within average-risk populations. Methods: Systematic review of randomised controlled trials comparing folic acid alone, or with other agents, versus placebo. Eight databases were searched for relevant trials. Meta-analysis was performed. Results: The literature search retrieved 3785 citations. Six studies met the inclusion criteria. Meta-analysis of 3 studies in individuals with a history of adenomas showed no statistically significant difference in the relative risk of adenoma recurrence (RR0.93, p=0.27). A sensitivity analysis of the 2 higher quality trials changed the direction of effect (RR1.16, p=0.11). Meta-analysis of 3 trials in general populations demonstrated no statistically significant effect on the relative risk of colorectal cancer (RR 1.13, p=0.54). In all 3 analyses outcome event rates were higher in individuals receiving folic acid. Conclusions: There is no evidence that folic acid is effective in the chemoprevention of colorectal adenomas or colorectal cancer for any population.

Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis

            (Collin, Metcalfe et al. 2009) Download

Folate-pathway gene polymorphisms have been implicated in several cancers and investigated inconclusively in relation to prostate cancer. We conducted a systematic review, which identified nine case-control studies (eight included, one excluded). We also included data from four genome-wide association studies and from a case-control study nested within the UK population-based Prostate Testing for Cancer and Treatment study. We investigated by meta-analysis the effects of eight polymorphisms: MTHFR C677T (rs1801133; 12 studies; 10,745 cases; 40,158 controls), MTHFR A1298C (rs1801131; 5 studies; 3,176 cases; 4,829 controls), MTR A2756G (rs1805087; 8 studies; 7,810 cases; 37,543 controls), MTRR A66G (rs1801394; 4 studies; 3,032 cases; 4,515 controls), MTHFD1 G1958A (rs2236225; 6 studies; 7,493 cases; 36,941 controls), SLC19A1/RFC1 G80A (rs1051266; 4 studies; 6,222 cases; 35,821 controls), SHMT1 C1420T (rs1979277; 2 studies; 2,689 cases; 4,110 controls), and FOLH1 T1561C (rs202676; 5 studies; 6,314 cases; 35,190 controls). The majority (10 of 13) of eligible studies had 100% Caucasian subjects; only one study had <90% Caucasian subjects. We found weak evidence of dominant effects of two alleles: MTR 2756A>G [random effects pooled odds ratio, 1.06 (1.00-1.12); P = 0.06 (P = 0.59 for heterogeneity across studies)] and SHMT1 1420C>T [random effects pooled odds ratio, 1.11 (1.00-1.22); P = 0.05 (P = 0.38 for heterogeneity across studies)]. We found no effect of MTHFR 677C>T or any of the other alleles in dominant, recessive or additive models, or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on advanced or localized cancers. Our meta-analysis suggests that known common folate-pathway single nucleotide polymorphisms do not have significant effects on susceptibility to prostate cancer.

Selenium, Folate, and Colon Cancer

            (Connelly-Frost, Poole et al. 2009) Download

Selenium is an essential trace element that has been implicated in cancer risk; however, study results have been inconsistent with regard to colon cancer. Our objectives were to 1) investigate the association between selenium and colon cancer, 2) evaluate possible effect measure modifiers, and 3) evaluate potential biases associated with the use of postdiagnostic serum selenium measures. The North Carolina Colon Cancer Study is a large population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 (n = 1,691). Nurses interviewed patients about diet and lifestyle and drew blood specimens, which were used to measure serum selenium. Individuals who had both high serum selenium (> 140 mcg/l) and high reported folate (> 354 mcg/day) had a reduced relative risk of colon cancer [odds ratio (OR) = 0.5, 95% confidence interval (CI) = 0.4-0.8). The risk of colon cancer for those with high selenium and low folate was approximately equal to the risk among those with low selenium and low folate (OR = 1.1, 95% CI = 0.7-1.5) as was the risk for those with low selenium and high folate (OR = 0.9, 95% CI = 0.7-1.2). We did not find evidence of bias due to weight loss, stage at diagnosis, or time from diagnosis to selenium measurement. High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study.

Nutritional interpretation of folic acid interventions

            (Dary 2009) Download

Folate is an essential micronutrient, and its nutritional inadequacy is widespread; hence, programs to increase its intake are necessary. However, many concerns about possible adverse effects due to excesses have been raised. Serum folate levels are directly correlated with intake and, when low, are associated with neural tube defects (NTD), high blood homocysteine levels, and megaloblastic anemia. Serum folate cutoff points have been identified for each abnormality, and all can be associated with intakes related to the current recommended dietary parameters. Likewise, high intakes that overwhelm the physiological capacity to process folic acid into biologically active folate derivatives are near the recommended tolerable upper intake level. Although we do not know with certainty the minimum efficacious dose that prevents all folate-dependent NTD, it may actually be much lower than the current recommendation, especially when provided through food fortification; supplemental intakes around 100 microg/day appear to be appropriate.

Cancer incidence and mortality after treatment with folic acid and vitamin B12

            (Ebbing, Bonaa et al. 2009) JAMA Download

CONTEXT: Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. OBJECTIVE: To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. DESIGN, SETTING, AND PARTICIPANTS: Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. INTERVENTIONS: Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721). MAIN OUTCOME MEASURES: Cancer incidence, cancer mortality, and all-cause mortality. RESULTS: During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION: Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00671346.


Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele

            (Ericson, Ivarsson et al. 2009) Download

BACKGROUND: Folate is involved in DNA synthesis and methylation and may thereby influence carcinogenesis. OBJECTIVES: We examined plasma folate (P-folate) concentration in relation to genotypes of the folate-metabolizing enzyme methylenetetrahydrofolate reductase [MTHFR 677C-->T (rs1801133) and 1298A-->C (rs1801131)]. We also explored whether P-folate was associated with risk of postmenopausal breast cancer overall and in subgroups with genetic variants of the MTHFR single nucleotide polymorphisms (SNPs). DESIGN: This nested case-control study included 313 cases (age 55-73 y at baseline) with invasive breast cancer and 626 control subjects, matched on age and blood-sample date, from the population-based Malmo Diet and Cancer cohort. P-folate and MTHFR genotypes were determined for 310 cases and 611 controls. P-folate according to genotype was calculated by using analysis of variance. Odds ratios were obtained by using logistic regression. All tests were 2-sided. RESULTS: The variant 677T allele was associated with lower P-folate. In women with the 677T allele, a high P-folate concentration was associated with increased breast cancer risk (P for trend across P-folate tertiles = 0.03). Interaction was seen between the 677C-->T SNP and P-folate (P = 0.002). A positive association, which was seen between P-folate and breast cancer risk in 1298AA women (P = 0.01), was probably due to linkage between the 2 SNPs. Overall, and in women with other genotypes, no significant associations were observed. CONCLUSIONS: Our results suggest an association of high P-folate concentration with increased risk of postmenopausal breast cancer in carriers of the 677T allele. The findings underline the importance of genetic variation of MTHFR in the complex relation between folate and cancer.

Folic Acid Supplementation and Colorectal Cancer Risk; A Meta-analysis

            (Fife, Raniga et al. 2009) Download

Abstract Aim: This meta-analysis aims to determine the effect of folic acid supplementation on colorectal cancer risk. Methods: A structured search of the MEDLINE, EMBASE, Cochrane, CINAHL databases was undertaken in July 2008 . All published full text English-language articles that included a randomised or pseudo-randomised comparison of subjects who received folate versus subjects who did not in relation to their risk of adenoma or advanced adenomatous lesions including colorectal cancer. A weighted treatment effect (using fixed effects) was calculated across trials Results: Overall the risk of an adenomatous lesion was not increased (OR=1.09, 0.93-1.28) among patients who received folate supplementation for up to 3 years, however for those who received folate for over three years the risk of an adenomatous lesion was increased (OR=1.35, 1.06-1.70). The risk associated with treatment was highest for the occurrence of an advanced lesion (1.50, 1.06 - 2.10). There was no significant statistical heterogeneity in the analyses. Conclusion: At the three-year colonoscopic follow-up folate supplementation had no effect on adenoma recurrence overall. While colonic surveillance beyond three years revealed an increased risk of colorectal adenoma especially advanced adenomas among those participants randomised to the folate group. This meta-analysis challenges the results from epidemiological studies that folate status is inversely related to the risk of developing colorectal cancer.

Folate and colorectal cancer: an evidence-based critical review

            (Kim 2007) Download

Currently available evidence from epidemiologic, animal, and intervention studies does not unequivocally support the role of folate, a water-soluble B vitamin and important cofactor in one-carbon transfer, in the development and progression of colorectal cancer (CRC). However, when the portfolio of evidence from these studies is analyzed critically, the overall conclusion supports the inverse association between folate status and CRC risk. It is becoming increasingly evident that folate possesses dual modulatory effects on colorectal carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on the progression of established colorectal neoplasms. In contrast, folate deficiency in normal colorectal mucosa appears to predispose it to neoplastic transformation, and modest levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses enhance, the development of cancer in normal colorectal mucosa. Several potential mechanisms relating to the disruption of one-carbon transfer reactions exist to support the dual modulatory role of folate in colorectal carcinogenesis. Based on the lack of compelling supportive evidence and on the potential tumor-promoting effect, routine folic acid supplementation should not be recommended as a chemopreventive measure against CRC at present.

Folate intake and the risk of colorectal cancer in a Korean population

            (Kim, Kim et al. 2009) Download

BACKGROUND: Folate, a water-soluble B vitamin and one of the major micronutrients in vegetables, is known as an essential factor for the de novo biosynthesis of purines and thymidylate, and it plays an important role in DNA synthesis and replication. Thus, folate deficiency results in ineffective DNA synthesis, and has been shown to induce the initiation and progression of colorectal cancer (CRC). Recently, the incidence of CRC in Korea has increased markedly in both men and women; this trend may be related to the adoption of a more 'westernized' lifestyle, including dietary habits. OBJECTIVE: A hospital-based case-control study was conducted to examine the relationship between folate intake and the risk of CRC within a Korean population. METHODS: A total of 596 cases and 509 controls, aged 30-79 years, were recruited from two university hospitals. Site- and sex-specific odds ratios (ORs) were estimated using logistic regression models. RESULTS: Cases were more frequently found to have a family history of CRC among first-degree relatives, to consume more alcohol, to be more likely current smokers and less likely to participate in vigorous physical activity than the controls. In the overall data for men and women combined, multivariate ORs (95% confidence interval (CI), P for trend) comparing the highest vs the lowest quartile of dietary folate intake were: 0.47 (0.32-0.69, <0.001) for CRC, 0.42 (0.26-0.69, <0.001) for colon cancer and 0.48 (0.28-0.81, 0.007) for rectal cancer. An inverse association was also found in women with dietary folate intake: 0.36 (0.20-0.64, <0.001) for CRC, 0.34 (0.16-0.70, 0.001) for colon cancer and 0.30 (0.12-0.74, 0.026) for rectal cancer, but not in men. In addition, the total folate intake of women was strongly associated with a reduced risk of rectal cancer (OR, 0.38; 95% CI, 0.17-0.88; P for trend=0.04). CONCLUSION: We found a statistically significant relationship between higher dietary folate intake and reduced risk of CRC, colon cancer and rectal cancer in women. A significant association is indicated between higher total folate intake and reduced risk of rectal cancer in women.

Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons

            (Mason 2009) Download

Evidence indicates that an abundant intake of foodstuffs rich in folate conveys protection against the development of colorectal cancer, and perhaps some other common cancers as well. The issue is complex, however, since some observations in animal and human studies demonstrate that an overly abundant intake of folate among those who harbor existing foci of neoplasia might instead produce a paradoxical promotion of tumorigenesis. The pharmaceutical form of the vitamin, folic acid, might affect the process in a manner that is distinct from natural forms of the vitamin, although this remains a speculative concept. Our limited understanding of this complex relationship is impeding efforts to move ahead with widespread folic acid fortification, but this delay may be necessary to ensure that such programs are instituted in a safe manner.

Getting folic acid nutrition right

            (Rosenberg 2009) Download

Too much folate: a risk factor for cancer and cardiovascular disease?

            (Sauer, Mason et al. 2009) Download

PURPOSE OF REVIEW: The intent of this evidence-based review is to analyze the role of folate in chronic diseases, focusing on cancer and cardiovascular disease. RECENT FINDINGS: Low folate status has been shown to be a risk factor for cancer and cardiovascular disease. Although epidemiological data suggest an inverse association between folate status and disease risk, intervention studies give equivocal results, suggesting the response to folate intake does not follow a linear continuum. Moreover, recent folate intervention trials raise concern about possible adverse effects of folate supplementation and suggest that too much folate in inopportune settings may be potentially harmful in individuals at higher risk for cardiovascular disease and cancer. SUMMARY: Although folate intake at sufficient levels appears to be an effective cancer chemopreventive strategy, high-dose supplementation of folate has generally not been effective in reducing recurrence of cardiovascular events or colorectal adenomas in clinical intervention trials. Although controversial, high folate status achieved through folate fortification or supplementation may increase the risk of certain chronic diseases among certain individuals, possibly by interfering with the homeostasis of one-carbon metabolism. Further research is urgently needed to accurately define the relationship between supraphysiological intake of folate and chronic diseases.

Folate intake and prostate cancer risk: a case-control study

            (Shannon, Phoutrides et al. 2009) Download

Folate deficiency has been implicated in the carcinogenesis of several tumor types. The role of folate in prostate cancer remains indeterminate. We investigated folate as a risk factor for prostate cancer among 140 biopsy-confirmed prostate cancer patients, 230 age-matched clinic controls, and 250 negative prostate biopsy controls. Dietary folate intake was inversely associated with overall risk of prostate cancer as compared to clinic controls (P for a linear trend = 0.003). When stratified by disease severity, dietary folate and folate from natural sources were associated with reduced risk of high-grade cancer as compared to both clinic controls (P for a linear trend = 0.0009 and 0.02, respectively) and biopsy negative controls (P for a linear trend = 0.03 and 0.05, respectively). There was no interaction between alcohol consumption and folate intake. These analyses support an inverse association between dietary folate intake and prostate cancer risk and primarily risk of high-grade prostate cancer.

A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma

            (Wu, Platz et al. 2009) Download

BACKGROUND: Evidence from observational studies suggests that inadequate folate status enhances colorectal carcinogenesis, but results from some randomized trials do not support this hypothesis. OBJECTIVE: To assess the effect of folic acid supplementation on recurrent colorectal adenoma, we conducted a cost-efficient, double-blind, randomized trial among participants of 2 large prospective cohorts, the Health Professionals Follow-Up Study and the Nurses' Health Study. DESIGN: Participants were randomly assigned to receive folic acid (1 mg/d) (n = 338) or placebo (n = 334) for 3-6.5 y. The primary endpoint was any new diagnosis of adenoma during the study period (May 1996-March 2004). Secondary outcomes were adenoma by site and stage and number of recurrent adenomas. Associations were also examined by plasma folate concentrations at baseline. RESULTS: Incidence of at least one recurrent adenoma was not significantly associated with folic acid supplementation [relative risk (RR): 0.82; 95% CI: 0.59,1.13; P = 0.22]. Among participants with low plasma folate concentrations at baseline (<or=7.5 ng/mL), those randomly assigned to receive folic acid experienced a significant decrease in adenoma recurrence (RR: 0.61; 95% CI: 0.42, 0.90; P = 0.01), whereas for subjects with high folate concentrations at baseline (>7.5 ng/mL), supplemental folic acid had no significant effect (RR: 1.28; 95% CI: 0.82, 1.99; P = 0.27, P(interaction) = 0.01). Contrary to findings from another clinical trial, there was no evidence for an increased risk of advanced or multiple adenomas. CONCLUSIONS: Our results do not support an overall protective effect of folic acid supplementation on adenoma recurrence. Folic acid supplementation may be beneficial among those with lower folate concentrations at baseline. This trial was registered at clinical trials.gov as NCT00512850.


References

Altmae, S., A. Stavreus-Evers, et al. (2009). "Variations in folate pathway genes are associated with unexplained female infertility." Fertil Steril.

Carroll, C., K. Cooper, et al. (2010). "Meta-analysis: folic acid in the prevention of colorectal adenomas and the chemoprevention of colorectal cancer." Aliment Pharmacol Ther.

Collin, S. M., C. Metcalfe, et al. (2009). "Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis." Cancer Epidemiol Biomarkers Prev 18(9): 2528-39.

Connelly-Frost, A., C. Poole, et al. (2009). "Selenium, folate, and colon cancer." Nutr Cancer 61(2): 165-78.

Dary, O. (2009). "Nutritional interpretation of folic acid interventions." Nutr Rev 67(4): 235-44.

Ebbing, M., K. H. Bonaa, et al. (2009). "Cancer incidence and mortality after treatment with folic acid and vitamin B12." JAMA 302(19): 2119-26.

Ericson, U. C., M. I. Ivarsson, et al. (2009). "Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele." Am J Clin Nutr 90(5): 1380-9.

Fife, J., S. Raniga, et al. (2009). "Folic Acid Supplementation and Colorectal Cancer Risk; A Meta-analysis." Colorectal Dis.

Kim, J., D. H. Kim, et al. (2009). "Folate intake and the risk of colorectal cancer in a Korean population." Eur J Clin Nutr 63(9): 1057-64.

Kim, Y. I. (2007). "Folate and colorectal cancer: an evidence-based critical review." Mol Nutr Food Res 51(3): 267-92.

Mason, J. B. (2009). "Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons." Nutr Rev 67(4): 206-12.

Rosenberg, I. (2009). "Getting folic acid nutrition right." Am J Clin Nutr 91(1): 3-4.

Sauer, J., J. B. Mason, et al. (2009). "Too much folate: a risk factor for cancer and cardiovascular disease?" Curr Opin Clin Nutr Metab Care 12(1): 30-6.

Shannon, J., E. Phoutrides, et al. (2009). "Folate intake and prostate cancer risk: a case-control study." Nutr Cancer 61(5): 617-28.

Wu, K., E. A. Platz, et al. (2009). "A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma." Am J Clin Nutr 90(6): 1623-31.

Yang, Q., R. M. Bostick, et al. (2009). "Serum folate and cancer mortality among U.S. adults: findings from the Third National Health and Nutritional Examination Survey linked mortality file." Cancer Epidemiol Biomarkers Prev 18(5): 1439-47.