Can This Folate-Metabolizing Gene Increase Your Risk Of Headaches And Migraines? (MTHFR)

The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase or MTHFR. This enzyme is responsible for converting dietary folate into available active folate, which is essential for the conversion of the amino acid homocysteine to methionine [R, R].

This enzyme is also important for the production of DNA and methylation pathways that are essential for all bodily functions [R].

Low MTHFR activity can lead to increased homocysteine, an inflammatory amino acid. Elevated homocysteine can wreak havoc on your health; it has been linked to cardiovascular disease, reduced brain function, and autoimmunity [R, R, R, R].

The MTHFR gene encodes MTHFR enzymes, which are essential for the conversion of homocysteine into methionine. Low MTHFR levels may promote homocysteine buildup, which may cause inflammation.

Headaches are unpleasant pains in your head associated with aching and pressure, and may be caused by malfunctions of the nervous system. Persistent headaches are the primary symptom of migraines, and typically the head pain associated with them is worse. For migraines, head pain is felt alongside symptoms such as [R]:

• Nausea
• Sickness
• Seeing flashing lights or spots
• Light and sound sensitivity
• Loss of sight

Migraines can be further subdivided into migraines with and without aura. Migraines with aura affect roughly 25% of migraine sufferers. These are categorized by migraine-preceding symptoms such as seeing blind spots, seeing flashing lights, or hearing noises that aren’t there. Conversely, migraines without aura come on without prior warning [R].

One of the main causes of headaches and migraines is inflammation. One source of chronic inflammation leading to head pain is thought to be vascular (blood vessel) dysfunction. 

This dysfunction can be observed as poor vasodilation (widening of blood vessels).

Head pain, in the form of headaches or migraines, can be caused by blood vessel dysfunction and accompanying inflammation.

Multiple studies have associated carrying a variant of the MTHFR gene with risk of head pain.

rs1801133

A group of researchers investigated the relationship between the common MTHFR gene variant rs1801133 and migraine risk in white people. They did so first by comparing the genes of 1402 people without migraines to 447 people with migraines. This was then followed with a meta-analysis of more than 34,000 individuals across 15 studies [R].

The investigators found an association between carrying the ‘A’ allele of the variant and an increased risk of migraine with aura [R].

This association was also found by two additional meta-analyses. One of the two studies only observed the association in non-white individuals [R, R].

The ‘A’ allele of rs1801133 has also been found to be associated with an increased risk of chronic cluster headaches [R].

Despite these associations, some studies have found there to be either no effect or even a protective effect of the ‘A’ allele on migraine risk. This may be due to differences in study design, and so further studies with more participants are required to confirm the relationship between MTHFR variants and migraine risk [R, R].

The ‘A’ allele of rs1801133 has also been shown to be associated with symptoms of the chronic pain condition fibromyalgia [R].

rs1801131

One research group has also investigated the link between rs1801131 and migraines. They did this by conducting a meta-analysis involving 26 studies. The 26 studies totalled 10,228 migraine sufferers and 28,608 healthy controls [R]. 

The group reported an association between individuals carrying two copies of the ‘G’ allele, and an increased risk of migraine without aura in white and indian individuals [R].

MTHFR gene variants may increase an individual’s susceptibility to headaches and migraines.

How MTHFR Variants May Increase Headache And Migraine Risk

Functioning normally, the MTHFR gene facilitates healthy blood folate and homocysteine levels. These, in turn, promote the availability of nitric oxide. Nitric oxide is important in the maintenance of healthy vascular function and has also been shown to act as an anti-inflammatory molecule in rodents [R, R].

Both of the MTHFR variants associated with head pain produce enzymes with reduced activity.

The rs1801133 MTHFR variant ‘A’ allele produces an enzyme with 40-70% reduced activity [R, R].

The ‘CC’ genotype of rs1801131 has been associated with a 60% reduction in enzyme activity in comparison to ‘AA’ carriers [R, R].

The reduced MTHFR enzyme activity may reduce folate availability and increase homocysteine levels. Excess homocysteine may cause vascular dysfunction by reducing the availability of nitric oxide, which can lead to excessive vasodilation [R, R, R].

Supporting this theory is the fact that a group of individuals suffering from migraine with aura were found to have increased blood vessel dilation. However, further research is required to confirm the mechanism behind MTHFR and migraine [R].

Impaired MTHFR enzyme activity associated with MTHFR variants may increase the risk of head pain by causing vascular dysfunction, leading to inflammation.

SNP Summary and Table

MTHFR rs1801133

• ‘AA’ = Increased risk of migraine with aura [R]
• ‘AG’ = Increased risk of migraine with aura [R]
• ‘GG’ = Normal risk of migraine

41% of individuals carry at least one copy of the ‘A’ allele [R].

MTHFR rs1801131

• ‘GG’ = Increased risk of migraine without aura [R] 
• ‘GT’ = Normal risk of migraine [R]
• ‘TT’ = Normal risk of migraine

7% of individuals carry two copies of the ‘G’ allele [R].