Folate Biomarkers, Folate Intake, and Risk of Death From All Causes, Cardiovascular Disease, and Cancer: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies

Abstract

CONTEXT: Existing evidence on the relation between folate intake and biomarkers with mortality risk is controversial. OBJECTIVE: Previous cohort studies were examined regarding folate intake and biomarkers in relation to risk of all-cause, cardiovascular disease- (CVD), and cancer-related mortality through a systematic review and meta-analysis. DATA SOURCES: A systematic search was performed of the PubMed, Scopus, and ISI Web of Science databases up to July 2023. DATA EXTRACTION: Prospective cohort studies examining the association of folate biomarkers (in serum, plasma, red blood cells) and intake with risk of all-cause, CVD-, and cancer-related mortality were considered. A random-effects model was applied to combine study-specific risk estimates. Dose-response relations were assessed by 1-stage weighted mixed-effects meta-analysis. DATA ANALYSIS: A total of 25 cohorts with 423 304 participants, 36 558 all-cause, 12 662 CVD-, and 2426 cancer-related deaths were included. No significant association was observed between the highest levels of folate biomarkers and all-cause mortality risk (hazard ratio HR, 0.91; 95% CI, 0.77-1.06; n = 17; I2 = 89.4%; P < .001), CVD-related mortality risk (HR, 0.97; 95% CI, 0.87-1.06; n = 11; I2 = 0.0%; P = .57), and cancer-related mortality risk (HR, 0.85; 95% CI, 0.69-1.05; n = 6; I2 = 57.8%; P = .04) compared with the lowest. Furthermore, each 10 nmol/L increase was marginally related to a 12% reduced all-cause mortality risk but not to CVD- and cancer-related mortality risk. A significant inverse association was found between highest intake of dietary folate and the lowest, and risk of all-cause (HR, 0.87; 95% CI, 0.78-0.96; n = 3; I2 = 63.6%; P = .06) and CVD (HR, 0.77; 95% CI, 0.57-0.93; n = 4; I2 = 80.2%; P = .002) mortality. CONCLUSIONS: This meta-analysis revealed a significant inverse relation between dietary folate intake and risk of all-cause and CVD mortality. Such an association was not found in the case of folate biomarkers. Further prospective studies are warranted to confirm these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023401700.