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