Folate Metabolism, Genetics, Pregnancy and Diet

As a toddler, we learn the song “Head and Shoulders, Knees and Toes, Eyes, Ears, Mouth and Nose“.  We recognize people by  their external characteristics – sex, voice, eye color, hair, and body size. Soon we learn that all people don’t all behave the same. It shouldn’t be surprising to realize that people differ on the inside too!

Genetic testing is frequently proposed as a means to identify risk for developing cancer or other inherited mutations associated with disease.

Folate [or folic acid the form used in food fortification and dietary supplements] is a B vitamin which is an essential to make nucleic acids (DNA & RNA), methionine regeneration (amino acid metabolism), and one-carbon units required for metabolism (Bailey & Gregory, 1999). 

The methylene tetrahydrofolate reductase (MTHFR) gene encodes for an enzyme, MTHFR, which is essential for folate metabolism. Because of a single amino acid substitution (valine for alanine), 3 common MTFHR polymorphisms are found in the human population: MTHFR 677 CC, MTHFR 677 CT, MTHFR 677 TT (Wang et al., 2016).

 Shane et al (2018) screened the entire human genome for common genetic polymorphisms that influence folate-status biomarkers in 2,232 young, healthy Irish university students. They report mean red blood cell (RBC) folate concentrations for women and men of 1058 and 1,099 nmol/L, respectively.  RBC folate concentrations were not distributed normally; presumably because they were higher in the 23% of the population using dietary supplements containing folic acid. The authors report:

Our studies clearly indicate that the MTHFR 677C→T (rs1801133) variant is the major genetic modifier of folate status biomarkers and may be the only significant modifier of serum (plasma) and red blood cell folate concentrations, at least in young, healthy adults in the Irish population.

Shane et al (2018) also write:

The T allele of MTHFR 677 causes decreases in both serum and red blood cell folate, the latter being a proxy for tissue folate, which would indicate an impairment in folate status.

But this is the clincher from their paper:

Because the poorer folate status caused by this variant is reflected in the changes in the concentrations of these biomarkers for folate status, there does not appear to be any added benefit in genotyping subjects for this variant (emphasis added) when interpreting folate status through the use of these biomarkers. Carriers of the T allele are also responsive to folate intake (31), which indicates that a T allele–dependent low folate status is responsive to treatment, also making genetic testing unnecessary.

The World Health Organization (WHO) recommendation for countries is that women of reproductive age should maintain RBC folate concentrations  >906 nmol/L to achieve the greatest reduction in NTDs.

The US and Canadian governments mandated folic acid fortification of flour in 1998. According to the CDC, this legislation has prevented approximately 1,300 babies being born with NTDs in the US annually. Since mandatory fortification, mean RBC concentrations have risen significantly. 

Nevertheless, approximately 33% of women of childbearing age may still not achieve WHO recommended RBC folate concentrations.

Bottom Line

Genetic testing for MTHFR polymorphisms isn’t necessary. A simple blood test for RBC folate concentration will suffice to determine if folate status is adequate. 

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Pleased to be giving a seminar as an Adj

Pleased to be giving a seminar as an Adjunct Professor on “Personalizing Nutrition Guidance and Career Development” in the Department of Human Health & Nutritional Sciences, University of Guelph on Monday, Nov 19 at 1:00! HHNS at UofG http://ow.ly/i/JAWnz

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Standardization of methods so that resea

Standardization of methods so that research studies conducted in different labs can be compared ALWAYS helps science advance. This paper applies to doubly water labeling studies to measure energy expenditure & body composition http://ow.ly/45gD30mE0Dl

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New Hope in Recognizing Fictional Epidemiological Diet-Disease Discourse

In an insightful paper, Archer, Lavie and Hill (2018) argue that controversies regarding the health effects of dietary sugar, salt, fat and cholesterol are not driven by legitimate observations.

They discuss the fatal flaws of Memory-Based Dietary Assessment Methods (M-BMs):

  1. Dietary intake estimates are ‘mere guesswork’ and not accurate measurements of dietary intake.
  2. Human memory and dietary recall are not valid tools for objective data collection because people are forgetful, often intentionally misreport and change their responses to offer socially desirable responses.
  3. Conversion of abstract concepts/answers to categorical data is pseudo-scientific and misleading.
  4. M-BMs rely upon Food Frequency Questionnaires (FFQ) listing only 75-200 items or 24 hour recall data, both reliant upon incomplete food databases (the largest contains about 8,000 of >85,000 food items found in the marketplace) with varying degrees of analytical accuracy
  5. Studies using quantitative tools, e.g. doubly-labelled water, have found proxy estimates determined by M-BMs to be physiologically implausible

In short, the authors write:

“Thus, we posit that while dietary intake is an obvious and essential component of health, it is a trivial risk factor for obesity, metabolic, and chronic diseases.”

They go on to say:

“In fact, these estimates are so trivial, “crude and imprecise” that most diet-disease associations may be considered spurious (141). As such, we posit that measuring “diet” per se is tangential if not irrelevant to the major public health issues faced by industrialized nations.”

Archer, Lavie and Hill suggest that the answer may lie in metabolic differences among individuals, i.e. our ‘metabolic phenotype’. They acknowledge the resources required for metabolic phenotyping.

There may be an interim, more achievable nutrition goal.

Let’s shift our focus to objective measures of micronutrient status on chronic disease and away from an obsession with dietary sugar, fat, salt and cholesterol intake.

The fortification of food staples beginning in the 1940s (iodized salt, vitamin D fortified milk, B-vitamin fortification of cereal grains) has had a tremendous public health impact. However, society has changed. With >85,000 food items in the market, people eating on the go, and a diet-disease discourse that creates confusion and increases distrust of the agri-food industry, dietary patterns are becoming increasingly diverse. While overeating may be prevalent, lifestyle choices may increase risk of over- and underconsumption of essential nutrients.

Hidden hunger, a lack of essential vitamins and minerals to maintain health, occurs in people who are underweight, normal weight, or overweight/obese. Reports on the prevalence of hidden hunger often rely upon B-MBs. They need not. We should be adopting objective measures of nutritional status, i.e. serum 25(OH)D, serum ferritin, EPA+DHA, macular pigment density for lutein, etc.

Vitamin D is the poster nutrient for my recommendation. The National Institute of Standards and Technology (NIST) and National Institutes of Health established a Vitamin D Metabolites Quality Assurance Program. Based on this, nutrition and medical researchers have begun unravelling important relationships between vitamin D status and health (see two examples below).

Serum vit D and bone mineral densitySerum vit D and overall mortality

It is possible to objectively monitor health status using many objective biomarkers: body weight, blood pressure, blood vitamin levels, blood (or red blood cell membrane) fatty acids EPA+DHA, serum cholesterol, glycosylated hemoglobin, C-reactive protein, serun ferritin for iron, etc).

As seen in the figure below, we know that individual responses to a standardized vitamin D dosage differ. We can speculate about vitamin D-related polymorphisms but we still do not know why; mostly because individual responses have not been studied very broadly. 

A ‘metabolic phenotype’ may mean some individuals can consume more (or less) of a nutrient to maintain optimal micronutrient status. For most micronutrients, ‘optimal status’ is a vague term that needs to be defined further. However, if it is the availability of vitamins to cells, i.e. vitamin status, that affects cellular function and disease risk, then the dietary objective is to maintain ‘optimal status’ regardless of genetics. This hypothesis needs testing.

By adopting objective measures of nutritional status, nutrition scientists and medical scientists can unravel diet-disease relationships and help end our obsession with food. It is time to move forward…..

 

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In the USA, 28% of adults use multivitam

In the USA, 28% of adults use multivitamin-mineral supplements (MVMS) to increase nutrient intake (Blumberg et al, 2017). New research from China finds <1.8% using MVMS https://t.co/Ok9BrNNapX #MissedOpportunity #StatusMatters

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In the USA, 28% of adults regularly uses

In the USA, 28% of adults regularly uses (>21d/mo) multivitamin-mineral supplement (MVMS) to increase nutrient intake (Blumberg et al, 2017). New data from China finds <1.8% using MVMS http://ow.ly/DF7330mApv6 #MissedOpportunity #StatusMatters http://ow.ly/i/JuwRA

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20 Things to Know When Starting PhD Studies

Working toward a PhD, or ready to reflect on your own experience? Then you should read these 20 recommendations by Lucy A Taylor.

Number 8 is always a challenge for me. The thought of writing a thesis, a book chapter, or a research paper is daunting. In fact, it leads to LOTS of procrastination. It is so much easier to start with a small component.

When writing a research paper, I always start with the methods, then compile my data into tables and figures. Now I have the narrative for the results section. Then I write my conclusions. Now out of the 100 plus ways I could begin the introduction, only one really leads through the rationale and to the conclusions.

With respect to book chapters, it helps me to create an outline. Then I can write it section by section. The struggle of sequencing the sections and linking them is always the most difficult for me.

Blogging I find easier because the format is shorter. I focus on ‘what’ I want to say, the ‘why’ am I writing this. Who do I hope will read it? Why? What are they hoping to learn.

Today, there isn’t much to learn from my blog. It was best said by Lucy Taylor.

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