The Link Between Methylation & Dietary Requirements (MTRR)

What is MTRR?

The MTRR gene encodes an enzyme called methionine synthase reductase, or MTR. This enzyme enables MTR to turn homocysteine into methionine, using vitamins B12 and B2 [R, R].

Homocysteine clearance is one of the critical points of the methylation cycles, as elevated homocysteine can negatively affect heart health, metabolism, mental health, fetal development, and more [R, R].

Methylation: the Bigger Picture

Besides homocysteine clearance, the methylation cycle helps produce glutathione — the so-called "master" antioxidant — as well as supplies methyl groups that control gene expression. These reactions — collectively known as the one-carbon metabolism — are vital for many aspects of physical and mental health [R, R].

Two different pathways enable homocysteine clearance (see the image above):

• One uses folate and vitamin B12 and relies on MTR and MTRR enzymes.
• The other one uses betaine derived from choline.

Methionine obtained via these pathways helps produce phosphatidylcholine via the PEMT enzyme. This cycle reveals a close connection between the genes and enzymes involved in choline, folate & vitamin B12 metabolism [R, R].

Genes and enzymes involved in choline, folate, and vitamin B12 metabolism interconnect through a complex methylation cycle that removes homocysteine.

Homocysteine Levels & Vitamin B12 Requirements

The most studied SNP in the MTRR gene, rs1801394 (66A>G), has shown mixed results when it comes to homocysteine levels. Some studies observed a correlation between the “G” allele and slightly elevated homocysteine, while others found no link [R, R, R, R, R].

Another SNP in this gene, rs1532268, was associated with increased homocysteine in a study of 771 adults. People with the “T” allele had 14% higher levels, but only when vitamin B12 status was low [R].

Elevated homocysteine (hyperhomocysteinemia) is associated with:

• Heart disease [R, R]
• Alzheimer’s disease and dementia  [R, R]
• Insulin resistance and diabetes [R, R] 
• Depression [R, R] 
• Autoimmune disorders [R, R, R] 

Two MTRR variants, rs1801394 and rs1532268, may be associated with elevated homocysteine, depending on other factors such as vitamin B12 status.

Choline Requirements

In a trial of 75 women, rs1801394-G influenced the metabolism of dietary choline. In the presence of regular choline intake (480 mg/d), the women with this variant used more choline for phosphatidylcholine production at the expense of betaine production [R].

In this trial, increased daily intake (930 mg) restored betaine production from choline,  suggesting that people with this variant may benefit from consuming more choline. That said, the effect was significant only in non-pregnant women [R].

Clinical Significance

Fetal Development

The one-carbon metabolism is essential for fetal development. Hence, it's no surprise that MTRR variants, especially rs1801394, may correlate with:

• Neural tube defects [R, R]
• Congenital heart defects [R]
• Down syndrome [R, R]

However, a meta-analysis of 10 studies and 3,527 children failed to confirm the link between rs1801394 and neural tube defects [R].

In a trial of 153 children and their mothers, rs1801394 didn’t show a significant association with spina bifida (the most common neural tube defect). However, in a subgroup of mothers deficient in vitamin B12, the "GG" genotype correlated with 4.8x higher odds of spina bifida. A combination with the primary folate-related SNP, rs1801133, yielded 3x higher odds of spina bifida [R].

MTRR variants may correlate with various congenital disorders. The link between rs1801394 and neural tube defects depends on other genetic factors and vitamin B12 status.

Other

In line with the crucial roles of methylation in reproductive health, immunity, and mental health, studies have observed a potential link between MTRR rs1801394 and:

• Colorectal and other types of cancer [R, R]
• Male fertility issues (mostly in Asians) [R, R]
• ADHD in children [R]

How It Works

The primary SNP, rs1801394, changes one amino acid in the MTRR structure, diminishing its ability to bind and activate MTR. As a result, MTR clears homocysteine less efficiently [R].

When that pathway is slowed down, the body doesn’t produce enough phosphatidylcholine and thus spends more dietary choline for phosphatidylcholine production [R].

SNP Summary

Primary SNP:

MTRR rs1801394

• ‘A’ = not associated with methylation or dietary requirements
• ‘G’ = associated with impaired methylation and higher needs for choline & vitamin B12

Population Frequency: Around 44% of European descendants carry one and 30% carry both copies of the “G” allele. It’s much less common in East Asian and African populations.

Other Important SNP:

MTRR rs1532268

• ‘C’ = not associated with methylation or dietary requirements 
• ‘T’ = associated with impaired methylation and higher needs for vitamin B12

Population Frequency: Around 58% of European descendants carry the “T” allele. It’s less common in Africans (48%) and much less common in East Asians (24%).