Folate intake and biomarkers and risk of chronic disease

Abstract

Background: Folate status of the U.S. population significantly improved after folic acid fortification of enriched cereal-grain products in 1998. Recent evidence suggests that the increased folate levels may have impacts on the risk of chronic disease. The kidneys are known to be highly involved in folate metabolism. Reduced renal function may affect folate metabolism and play a role in the associations between folate and chronic disease. Objectives: The purpose of this study was to review key events regulating folate homeostasis along folate metabolic pathway. In addition, we examined the associations between folate intake and biomarker levels and the incidence of cancer, stroke and cardiovascular disease (CVD) and between folate biomarker levels and renal function among older adults in post-fortification years. Design: The Key Events Dose-Response Framework was used to review key steps of folate metabolism. Data of adult participants of the National Health and Nutrition Examination Survey 1999-2002 were used as the baseline data. Incidence of cancer, stroke and CVD were obtained from the linked Medicare and mortality files. The associations between folate intake and biomarker levels and incidence of cancer, stroke and CVD, and the associations between estimated glomerular filtration rate (eGFR) and folate biomarkers, serum unmetabolized folic acid (UMFA) and plasma homocysteine levels were assessed using Cox proportional hazards regression models and multivariable regression models, respectively. Results: The saturation of dihydrofolate reductase in the liver is the determining point regulating the release of UMFA in circulation. Lower red blood cell (RBC) folate levels and intake of dietary folate equivalents were associated with a higher cancer incidence. Lower RBC folate and serum folate levels were associated with a higher stroke incidence. No significant associations between folate and CVD were observed. In addition, reduced renal function was associated with higher RBC folate and plasma homocysteine levels among men and women, and higher prevalence of UMFA in blood among women. Conclusion: High intake of folate may disturb folate metabolism by overwhelming folate regulation mechanisms. Folate may play a protective role against cancer and stroke even at high levels in post-fortification years. Reduced renal function may be implicated in the increased blood folate concentrations.