Workshop on Metabolic Interactions between Folic Acid Excess and Vitamin B12 Deficiency

Event Details

Background

One-carbon metabolism is a crucial network of pathways involved in cellular methylation reactions and nucleotide biosynthesis. The network is regulated by and dependent on several micronutrients. Of these, folate (Vitamin B9) and vitamin B12 play central roles as cofactors in the network. In the last two decades, folic acid fortification policies and voluntary supplementation have increased folic acid intake. The cumulative folic acid intake from fortification, supplementation, diet and other sources can easily exceed the upper limit set forth for folic acid (1000 μg/day). Some observational studies suggest an interaction between elevated folate/folic acid levels and vitamin B12 metabolism, raising the concern that high folate/folic acid status may exacerbate biomarkers of vitamin B12 deficiency and cognitive decline in older adults taking multivitamin supplements. Another growing concern is the appearance of unmetabolized folic acid in nearly all serum samples from US populations, as seen in the NHANES screening program. The biological activity or longtime health implications of higher unmetabolized folic acid exposures are not clear. The biological premise and experimental evidence for establishing a causal effect for the consequences of elevated folic acid intake and the role of high folate status in modifying the effects of vitamin B12 deficiency are lacking, and most animal and in vitro studies aimed at addressing this issue have suffered from experimental study design limitations. Research consensus on the approaches to investigate folate/folic acid -vitamin B12 interactions are urgently needed to assess the safety aspects associated with potential excess intake of folic acid.

Objectives

Main objectives of the workshop are to deliberate on the potential causal mechanisms of excess folate/folic acid and Vit B12 deficiency, as well as potential biological effects of unmetabolized folic acid and to develop consensus on various basic and clinical experimental study designs, intervention strategies and experimental models, for exploring the biochemical mechanisms for these interactions.

Planning Members

Padma Maruvada (NIH/NIDDK)
Christopher Lynch (NIH/NIDDK)
Sharon Ross (NIH/NCI)
Giovanna Zappala (NIH/NIA)
Dan Raiten (NIH/NICHD)
Drew Bremer (NIH/NICHD)
Cindy Davis (NIH/ODS)
Nancy Potischman (NIH/ODS)
Essie Yamini (FDA/CFSA)
David Klurfeld (USDA/ARS)

Chairs

Patrick Stover (Texas A&M University)
Joel Mason (Tufts University)

Registration Deadline

July 30, 2019

Agenda

July 31, 2019

8:00 a.m. – 8:05 a.m.

Welcome Remarks
Stephen James, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK

8:05 a.m. – 8:15 a.m.

Welcome Remarks and Charges to the Participants
Padma Maruvada, NIDDK

8:15 a.m. – 8:30 a.m.

Overview
Joel Mason, Tufts University

Session 1: Strategies for Evaluating Risk of Nutrient Excess and Establishing Cause-and-Effect Relations from Observational Studies

8:30 a.m. – 9:00 a.m.

Framework for Evaluating Evidence Needed to Determine the Harmful Effects of Elevated Folic Acid Levels
Joe Rodricks, Ramboll Institute

9:00 a.m. – 9:30 a.m.

Evidence-based Medicine for Evaluating the Strengths of the Data from Observational Studies
Bradley Johnston, Dalhousie University

9:30 a.m. – 10:00 a.m.

Overview of Biochemical and Molecular Interactions between Folate and Vitamin B12
Patrick Stover, Texas A&M University

10:00 a.m. – 10:15 a.m.

Break

Session 2: Current Understanding about the Consequences of the Interaction between Excess Folic Acid and Vitamin B12 Deficiency from the Observational Studies: Prevailing Controversies

10:15 a.m. – 10:45 a.m.

Historic Perspective of Interactions between Folic Acid and Vitamin B12
Irwin Rosenberg, Tufts University

10:45 a.m. – 11:15 a.m.

Interactions between Folate Excess and Vitamin B12 Deficiency: Perspective 1
Ann Molloy, University of Dublin

11:15 a.m. – 11:45 a.m.

Interactions between Folate Excess and Vitamin B12 Deficiency: Perspective 2
Paul Jacques, Tufts University

11:45 a.m. – 12:15 p.m.

Accumulation of Folic Acid Metabolites from the NHANES Data
Christine Pfeiffer, Centers for Disease Control Prevention

12:15 p.m. – 1:00 p.m.

Lunch

Session 3: Biological Effects of Increased Levels of Folate/Folic Acid on Vitamin B12 Interactions as Supported by Current Evidence

1:00 p.m. – 1:30 p.m.

Impact of Folic Acid Supplementation in Pregnancy and Lactation
Debbie O’Connor, McGill University Health Centre

1:30 p.m. – 2:00 p.m.

New Evidence on Epigenetic Modification and Genomic Programming
Jacquetta Trasler, McGill University Health Centre

2:00 p.m. – 2:30 p.m.

Model Systems and Dose Effects
Amanda McFarlane, Health Canada

2:30 p.m. – 3:00 p.m.

Known and Unknown Effects of Folic Acid Excess
Richard Finnell, Baylor College of Medicine

3:00 p.m. – 3:30 p.m.

Evidence for Mechanistic Interaction between Excess Folate/Folic Acid and Vitamin B12 Interactions: Insights from Human and Animal Data
Martha Field, Cornell University

3:30 p.m. – 4:00 p.m.

Break

Session 4: Moderated Panel Discussion

Moderator: Cutberto Garza, Cornell University

Panelists: Irwin Rosenberg, Tufts University
Josh Miller, Rutgers University
Ralph Green, University of California, Davis
Regan Bailey, Purdue University
Jacob Selhub, Tufts University
Sally Stabler, University of Colorado Aurora

4:00 p.m. – 5:30 p.m.

Topics Covered

1. Observational studies suggest that folic acid may possess idiosyncratic functions not ascribed to the more physiological forms of folate (other than its role in the DHFR saturation): what are those functions, at what exposure levels of folic acid does this occur, and what are the at-risk groups?
2. Observational data suggests that an excess of folate exposure, regardless of its form, has adverse effects on B12 status: at what exposure levels does this occur, are there plausible biological mechanisms, and what are the at-risk groups?
3. Observational studies also suggest that an excess of folate exposure, regardless of the form ingested, may have adverse effects in addition to the concern raised in query #2. At what exposure levels do these adverse effects occur, what are the plausible biological mechanisms, and what are the at-risk groups?

5:30 p.m.

Adjournment

August 1, 2019

8:00 a.m. – 8:15 a.m.

Recap of Day 1
Joel Mason, Tufts University

8:15 a.m. – 8:30 a.m.

Breakout Session Goals and Expectations
Patrick Stover, Texas A&M University

8:30 a.m. – 10:30 a.m.

Breakout Sessions (select one)

1. What are the biological effects and health implications of free folic acid?
   Chairs: Jean-Louis Gueant, University of Lorraine and INSERM
   Richard Finnell, Baylor College of Medicine
2. What types of dose-response data are needed, including biological and physiological endpoints, to better understand the requirements and risks of excess folate?
   Chairs: Regan Bailey, Purdue University
   Yvonne Lamers, University of British Columbia
3. What types of dose-response data are needed, including the biological and physiological endpoints, to better understand the interactions between folate excess in B12 deficiency?
   Chairs: David Rosenblatt, McGill University Health Centre
   Barry Shane, University of California, Davis

10:30 a.m. – 11:00 a.m.

Break

11:00 a.m. – 12:00 p.m.

Breakout Session Reports

12:00 p.m. – 12:30 p.m.

Consensus - Building on the Research Strategies and Discussing Next Steps
Joel Mason, Tufts University
Patrick Stover, Texas A&M University

12:30 p.m.

Adjournment