Elsevier

Clinical Nutrition

Volume 37, Issue 6, Part A, December 2018, Pages 1926-1934
Clinical Nutrition

Meta-analyses
Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis

https://doi.org/10.1016/j.clnu.2017.10.010Get rights and content

Summary

Background & aims

To evaluate the controversies among the studies assessing the association between folic acid intake or folate status and colorectal cancer risk.

Methods

PubMed, Cochrane library and references of related articles were searched from January 2000 to September 2016. Studies on folic acid intake or folate status and colorectal cancer or adenoma risk were included. Full text review was conducted for potentially eligible studies. Quality assessment was performed. Random-effects meta-analysis was used to estimate risk ratio and 95% Confidence Intervals. Analysis was conducted by Comprehensive Meta-Analysis software.

Results

Folic acid supplement intake showed no significant effect on colorectal cancer risk in meta-analysis of randomized controlled trials, RR: 1.07 (95% CI: 0.86–1.43). The effect on risk was not significant in cohort studies either; RR = 0.96 (95% CI: 0.76–1.21). However, there was significant reduced colorectal cancer risk in total folate intake in cohort studies; 0.71 (95% CI: 0.59–0.86). Odds Ratio was also significantly reduced in case control studies; 0.77 (95% CI: 0.62–0.95). Nevertheless once folate status was measured as Red Blood Cell folate content, no significant effect on colorectal cancer risk was observed; 1.05 (95% CI: 0.85–1.30).

Conclusion

The differences in bioavailability and metabolism of synthetic folic acid and natural dietary folate as well as variation in the baseline characteristics of subjects and various methods of folate status assessment might be the main reasons for these controversies. Findings of present study highlight the importance of individualized folic acid supplement intake given the fact that the beneficiary effects of long term folic acid supplementation is not confirmed.

Introduction

Folic Acid (FA), known as folacin, pteroylglutamic acid or vitamin B9, is abundant in green leafy vegetables, legumes and grains in form of folate [1]. The preventive effect of FA supplementation on birth defects led to fortification with FA in over 50 countries [2]. This mandate has resulted in a lower incidence of neural tube defects and meanwhile an increase in serum folate concentration [3].

Considering the possible dual role of FA in CRC, i.e. protecting normal cells meanwhile promoting precancerous cell growth, numerous investigations have yielded controversial results on the beneficial effect of FA on the incidence of CRC. Some studies, including Randomized Controlled Trial (RCT) and cohort studies show beneficial effects of supplementary FA or dietary folate on the primary prevention of colorectal adenomas [4], [5], [6], [7], [8]. While a large RCT of seven years supplementation with FA, reported the need for further investigation to access the association of FA with higher risks of advanced adenomas [9]. Findings from this study highlighted the point that the transient increase in CRC incidence in the United States and Canada might be due to the implementation of FA fortification [10]. Supporting evidence by experimental studies shows that synthetic FA, with higher bioavailability compared to dietary folate, may lead to an elevated metabolized plasma FA [11], which is known as an inhibitor of natural killer cells cytokine inhibitors [12].

To date several meta-analysis have assessed the effect of FA supplementation on CRC risk. A recent meta-analysis of eight RCTs and another of combined analysis of three large RCTs did not find a significant effect on incidence of CRC [13], [14]. However small sample sizes, differences in applied methodology and insufficient follow up time are among the shortcoming of included RCTs. Also two other meta-analysis of 10 RCTs and six RCTs found no beneficial effect of FA on various types of cancer risk and chemo-prevention of CRC [1], [15]. Our analysis differs from the latter review studies in following aspects; 1) being a systematic review, 2) including more diverse population with longer follow-up time, 3) conducting stratified analysis based on FA supplement intake and blood levels/total/dietary folate.

Given the possible methodological insufficiency in so far performed meta-analysis, we hypothesized that a broader meta-analysis consisting of various related studies might be required to investigate the effect of FA supplementation and folate status on CRC risk. Therefore a systematic review and meta-analysis were conducted, not only including RCTs but also cohort and case control studies, to study firstly the impact of FA supplement intake and secondly that of folate status on CRC risk, in order to building a more consistent conclusion while addressing the root of discrepancies.

Section snippets

Study protocol and search strategy

This study was performed according to PRISMA-P guidelines (Moher et al., 2009). PubMed and Cochrane library were systematically searched for studies published from January 2000 to September 2016, in English language, which have evaluated the relation between the intake of FA supplementation or folate status with the risk of CRC or adenoma (Fig. 1). MeSH terms for literature extraction from online resources were designed as following: (“Colorectal Neoplasms” or “colorectal neoplasm” or

Folic acid supplement intake and CRC risk

Thirteen studies were included in final analysis, consisting of 35,761 subjects in RCTs and 1,926,520 in cohort studies. There was a significant publication bias in FA supplement subgroup, Egger bias: 1.67 (95% CI: 0.05–2.66, P = 0.01). No significant heterogeneity was observed in eligible cohort studies, I2 = 0.00 (Q: 0.25, Phet = 0.88). There was a significant heterogeneity among RCTs, I2 = 68.92 (Q: 25.84, Phet = 0.001). Studies with most extreme findings from the overall finding were

Discussion

We assessed the role of FA supplement intake and folate status in the risk of CRC or adenoma in a meta-analysis of RCTs, cohort and case control studies. The bioavailability and metabolism of synthetic FA and natural dietary folate are different [11], therefore a broader meta-analysis was conducted with separate FA and folate subgroups in analysis. To best of our knowledge, it is for the first time that a systematic review and meta analysis including all types of controlled studies was

Contribution

SM designed the study, carried out the study, ran the data analyses and prepared the first draft of manuscript. SD designed the study, conceived the study and edited the manuscript. GB, BZA, commented on study design, data analyses, inference of results and critically editing the manuscript. RD, JST and JSH participated in the study design, performed the statistical analyses and helped to draft the manuscript. All authors read and approved the final manuscript.

Conflict of interest

This study was financially supported by Research Vice Chancellor of Tabriz University of Medical Sciences (grant numbers: TBZMED.REC.1394.1193). The authors declare that they have no competing interests.

Acknowledgement

Authors wish to thank all staff in Tabriz Health Service Management Research Center for their help. Karin Sijtsma (UMCG) is appreciated for her assistance in designing search strategy. Authors thank Research Vice Chancellor of Tabriz University of Medical Sciences for financial support of the study.

References (58)

  • T.N. Wien et al.

    Cancer risk with folic acid supplements: a systematic review and meta-analysis

    BMJ Open

    (2012)
  • Y. Kim

    Folate: a magic bullet or a double edged sword for colorectal cancer prevention?

    Gut

    (2006)
  • S. Barua et al.

    Folic acid supplementation in pregnancy and implications in health and disease

    J Biomed Sci

    (2014)
  • Q.-Y. Gao et al.

    Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial

    Cancer Prev Res

    (2013)
  • E.J. Konings et al.

    Intake of dietary folate vitamers and risk of colorectal carcinoma

    Cancer

    (2002)
  • J.E. Lee et al.

    Folate intake and risk of colorectal cancer and adenoma: modification by time

    Am J Clin Nutr

    (2011)
  • C. Bird et al.

    Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps

    Cancer Epidemiol Biomarkers Prev

    (1995)
  • B.F. Cole et al.

    Folic acid for the prevention of colorectal adenomas: a randomized clinical trial

    JAMA

    (2007)
  • J.B. Mason et al.

    A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis

    Cancer Epidemiol Biomarkers Prev

    (2007)
  • J.C. Figueiredo et al.

    Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials

    Int J Cancer

    (2011)
  • T. Qin et al.

    Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials

    Sci Rep

    (2015)
  • C. Carroll et al.

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

    Aliment Pharm Ther J

    (2010)
  • A.R. Jadad et al.

    Bias in randomized controlled trials. Randomized controlled trials: questions, answers, and musings

    (2008)
  • G.J. Hankey et al.

    Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack results of a randomized placebo-controlled trial

    Stroke

    (2012)
  • J.M. Armitage et al.

    Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors

    JAMA

    (2010)
  • E. Lonn et al.

    Homocysteine lowering with folic acid and B vitamins in vascular disease

    N Engl J Med

    (2006)
  • J.E. Lee et al.

    Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case–control studies

    Cancer Causes Control

    (2012)
  • S.M. Zhang et al.

    Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women

    Am J Epidemiol

    (2006)
  • E.S. Schernhammer et al.

    Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer

    Gut

    (2010)
  • Cited by (60)

    • Activation of progesterone receptor is essential for folic acid-regulated cancer cell proliferation and migration

      2023, Journal of Nutritional Biochemistry
      Citation Excerpt :

      Since its role in one-carbon metabolism, folate has been extensively studied as a possible mechanism for cancer development. The relationship between folate intake and cancer risk remains uncertain as investigations have shown positive [14,15], negative [16,17], and neutral [18,19] associations. Epidemiological studies demonstrated an opposite relationship between folate sufficiency and the risks of some malignancies [9,14,29].

    • In situ electrodeposition of bismuth oxide nanowires @MWNT on the carbon fiber microelectrode for the sensitively electrochemical detection of folic acid

      2023, Talanta
      Citation Excerpt :

      To reduce the risk of these diseases, many health organizations recommend women to take 0.4 mg of synthetic folic acid daily in addition to consuming food folate from a varied diet. Serum folate concentrations increase by 0.94 ng/mL for every 0.1 mg/day increase in folic acid intake in women aged 20–35 years, and about double that in people aged 40–65 [13]. Every doubling of serum folate concentration roughly halves the risk of NTD.

    View all citing articles on Scopus
    View full text