Riboflavin (Vitamin B2), MTHFR, and Genetics

Riboflavin (vitamin B2) is a water-soluble vitamin that is a cofactor for many enzymes in the body. It is vital for energy production in the mitochondria and is also a key component of your body’s detoxification system.

This article explains how your body uses riboflavin and the genetic variants that increase your need for riboflavin. Interestingly, research shows that riboflavin is incredibly important for people with MTHFR variants.

What is riboflavin and why is it important?

Riboflavin, also known as vitamin B2, is synthesized from a ribose sugar bound to a flavin molecule. Thus the name ribo-flavin.

This is an essential vitamin for many important cellular functions. Riboflavin is the precursor to FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide), which are coenzymes involved in numerous vital functions in our bodies.

FAD is an essential component of the electron transport chain, which is how your body produces energy in the mitochondria.

  • FAD is important for producing energy both from carbohydrates and through fatty-acid oxidation.[ref]
  • FAD is also involved in detoxification as a cofactor for some CYP450 enzymes as well as for glutathione recycling. FAD can participate in many different reactions in the body because it can easily donate and accept electrons. It can exist in different redox states (FADH2, FADH).[ref]

Within the mitochondria, FAD and FMN are also integral to activating the various enzymes that protect cells from oxidative stress, thus making adequate riboflavin essential for healthy mitochondria. Conditions that are related to mitochondrial dysfunction and reliant on FAD and FMN include Parkinson’s disease, Alzheimer’s, migraines, Complex I deficiency, Alper’s syndrome, multiple sclerosis, and Kearns Sayre syndrome.[ref]

Riboflavin deficiency can also play a role in mitochondrial dysfunction in the development of cardiovascular problems.[ref]

Riboflavin also helps convert tryptophan to niacin (vitamin B3), which in turn activates vitamin B6.[ref]

What are the symptoms of riboflavin deficiency?

A lack of riboflavin can show up as:

  • angular cheilitis (cracks at the corners of the mouth)
  • anemia
  • burning mouth
  • sore throat
  • cataracts

Riboflavin deficiency can also cause problems with iron absorption, leading to iron-deficiency anemia.

Who is at risk? People more likely to suffer from riboflavin deficiency include the elderly, women on birth control, vegans, and alcoholics.[article] Breastfeeding women may also need more riboflavin because breast milk contains a lot of riboflavin and FAD.[ref]

For most people eating a balanced diet, a frank riboflavin deficiency is considered rare. Most people meet the recommended daily allowance of 0.9-1.3 mg/day.[ref]

However, there is a difference between not having a severe deficiency and getting an amount that is optimal for your specific needs, taking into account genetics and lifestyle.

Riboflavin absorption from foods and transport:

Riboflavin is found in dairy products, eggs, liver, enriched flour, and in minor amounts in other foods. The US RDA is 1.6mg for adults, and most people are estimated to meet this with their daily food consumption.

Riboflavin is absorbed from foods as they are broken down in the upper part of the small intestines, so people with intestinal disorders that inhibit absorption could have problems with riboflavin deficiency.

Additionally, riboflavin must be transported within cells and into the mitochondria. Riboflavin-specific transporters are found on the outer membrane of the mitochondria. Rare mutations in this transporter (SLC52A2 gene) cause Brown-Vialetto-Van Laere syndrome, which is a rare neurological order that may be helped by riboflavin supplementation in some cases.[ref]

Benefits of supplemental riboflavin:

Clinical trials are an excellent way to know if a supplement is effective for most people. Genetic variants (below) can also clue you in as to whether you may need more riboflavin than normal.

Here’s what randomized clinical trials show:

Numerous studies and clinical trials have investigated high-dose riboflavin supplementation for migraines. While riboflavin may not be a panacea for everyone with migraines, it is inexpensive, non-toxic, safe, and effective for some migraine sufferers. For example, one study found that 400 mg/day of riboflavin cut migraine frequency in half after three months of treatment. (This is better than trial outcomes for many expensive migraine prescription medications and injections that have serious side effects!).[ref][ref][ref]

Eye health:
Riboflavin is also being investigated and used for preventing cataracts.[ref][ref]

Throat health:
Riboflavin is also important in the esophageal mucosa. A study in China examined the effects of using riboflavin-fortified salt in certain townships. The groups that received the riboflavin-fortified salt had lower rates of esophageal cancer.[ref]

Inflammatory Bowel Disease:
In patients with Crohn’s disease, riboflavin (100mg/day) decreased inflammatory markers significantly in three weeks.[ref]

Riboflavin supplementation and safety:

Vitamin B2, riboflavin, is a water-soluble vitamin. There is no known toxicity for taking too much riboflavin and no upper limit set in the US.[ref]

Excess riboflavin is excreted out through the kidneys and makes your pee yellow — really yellow.[ref]

Riboflavin Genotype Report:

Several genetic variants may cause an increased need for riboflavin. You can check your raw genetic data to see if you carry SNPs related to riboflavin deficiency.

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MTHFR gene: codes for the enzyme needed to convert folate to methylfolate, a key component in the methylation cycle.

Check your genetic data for rs1801133 C677T (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%
  • A/A: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

Members: Your genotype for rs1801133 is .

The C677T variant causes a change in the shape of the MTHFR enzyme and decreases its ability to bind to FAD.[ref] If you have high homocysteine (a marker for heart disease risk), several studies show that increasing riboflavin lowers homocysteine levels in those with the A/A genotype.[ref][ref] Other research points to riboflavin lowering homocysteine levels only if vitamin B6 levels are adequate.[ref]

Related Article: Vitamin B6 Genes

Additional research shows that low riboflavin status in women with MTHFR C677T increases the risk of fractures in osteoporosis.[ref][ref]

For those with the A/A genotype and high blood pressure, riboflavin (1.6 mg/day) lowered systolic blood pressure by 5 – 13 mmHg.That is pretty significant…[ref]

FMO3 Gene:
FMO3 (flavin-containing monooxygenase 3) variants can cause a decrease in the FMO3 enzyme, which breaks down certain nitrogen-containing amines and some sulfur-containing compounds. FMO3 is the primary way that the body breaks down trimethylamine. Decreased FMO3 activity can cause an increase in trimethylamine, which causes a fishy-smelling body odor.[ref] Some people with mild FMO3 variants are helped with riboflavin.[ref]
These first four variants are more significant reductions in enzyme activity and are linked to TMAU (fish odor or strong body odor). Note that 23andMe doesn’t cover all the FMO3 variants that decrease the function.

Related article: Trimethylaminuria (TMAU) and fish odor syndrome genes

Check your genetic data for rs61753344 (23andMe v4, v5: AncestryDNA):

  • T/T: decreased FMO3 function[ref]
  • G/T: decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs61753344 is .

Check your genetic data for rs1736557 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased FMO3 function[ref]
  • A/G: decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs1736557 is .

Check your genetic data for rs3832024 (23andMe v5):

  • DD or -/-: decreased FMO3 function [ref]
  • DI or -/TG: decreased FMO3 function
  • II or TG/TG: typical FMO3 function

Members: Your genotype for rs3832024 is .

Check your genetic data for rs2266780 (23andMe v4, v5; AncestryDNA):

  • G/G: somewhat decreased FMO3 function [ref]
  • A/G: somewhat decreased FMO3 function
  • A/A: typical FMO3 function

Members: Your genotype for rs2266780 is .

Check your genetic data for rs2266782 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased FMO3 function[ref][ref]; increased risk of hypertension, especially in smokers[ref]
  • A/G: somewhat decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs2266782 is .

Check your genetic data for rs909530 (23andMe v4 only):

  • T/T: somewhat decreased FMO3 function[ref] (probably mild)
  • C/T: somewhat decreased FMO3 function
  • C/C: typical FMO3 function

Members: Your genotype for rs909530 is .

Check your genetic data for rs909531 (23andMe v4 only):

  • C/C: somewhat decreased FMO3 function[ref]
  • C/T: somewhat decreased FMO3 function
  • T/T: typical FMO3 function

Members: Your genotype for rs909531 is .

The electron transport chain is how your body produces most of its energy, in the form of ATP, in the mitochondria of all of your cells. This process is dependent on the FAD molecule, which is a flavin-containing molecule. ETFDH codes for the electron-transferring-flavoprotein dehydrogenase, an enzyme that transfers electrons from FAD within the electron transport chain. There are a few rare mutations that disrupt this enzyme, causing decreased energy production.[ref]

Check your genetic data for rs121964954 (23andMe i5007876 v4; AncestryDNA):

  • A/A: a mutation that causes multiple acyl-CoA dehydrogenase deficiency
  • A/G: possibly pathogenic for multiple acyl-CoA dehydrogenase deficiency, riboflavin responsive[ref][ref]
  • G/G: typical

Members: Your genotype for rs121964954 is or for i5007876 is .

SLC52A3 Gene: (Riboflavin transporter, also known as C20Orf54)
The mutation listed below is possibly pathogenic for Brown-Vialetto-Van Laere, a rare neurological condition that is often normalized by high-dose riboflavin.[ref]

Check your genetic data for rs267606684 (23andMe i5008314 v4; AncestryDNA):

  • A/G: Brown-Vialetto – Van Laere syndrome possible[ref]
  • G/G: typical

Members: Your genotype for rs267606684 is or for i5008314 is .

SLC52A2 Gene: Riboflavin transporter in the mitochondria

Check your genetic data for rs782345472 (23andMe v5):

  • T/T: Brown-Vialetto-Van Laere syndrome mutation[ref]
  • C/T: carrier of Brown-Vialetto-Van Laere syndrome
  • C/C: typical

Members: Your genotype for rs782345472 is .

Check your genetic data for rs375088539 (AncestryDNA):

  • T/T: Brown-Vialetto-Van Laere syndrome mutation[ref]
  • C/T: carrier of Brown-Vialetto-Van Laere syndrome
  • C/C: typical

Members: Your genotype for rs375088539 is .

SLC25A32 Gene: (encodes the mitochondrial FAD transporter)

Check your genetic data for rs147014855 (23andMe v4):

  • C/T: possibly pathogenic for exercise intolerance, responsive to riboflavin[ref][ref]
  • C/C: typical

Members: Your genotype for rs147014855 is .

Lifehacks for boosting riboflavin:

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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