Like many kids, I grew up with a parent who suffered from debilitating migraines. I learned early on the importance of keeping noise, lights, stress, and smells to a minimum on a migraine day, despite not suffering from migraines myself. I know I’m not alone in this experience, given that around 11-15% of the population suffers with migraines. (R)(R)
Migraine is a central nervous system disorder characterized by a severe, piercing headache, usually around the eye and in the temples and typically on just one side of the head. There’s no single cause for migraines — your genes, environment, diet, and lifestyle all affect your risk for the condition. However, migraines are most prevalent in women between the ages of 25 and 45 and, overall, women are three times more likely than men to experience migraines. (R)(R) And, if you have a first-degree relative who suffers from migraines, you are almost twice as likely as average to experience migraines yourself, which certainly suggests a genetic component to the disease.
Because migraines are not associated with any clearly identifiable pathological changes to brain tissue, research into the causes of migraines has focused largely on vascular and neurogenic pathways, as well as the interaction between our genes, nutrition, and environment. Let’s take a deeper look at some of these causes and how nutrigenomics can help us relieve and even prevent migraines.
Your genes and migraines
In the 1960s, scientists found that migraineurs (someone who suffers from migraine headaches) had high levels of a urinary metabolite called 5-hydroxyindoleacetic acid (5-HIAA), suggesting that an inborn mutation in metabolism might play a role in the disease. 5-HIAA is the main metabolite of serotonin, a neurotransmitter involved in regulating mood and appetite. (R)
Since these early studies, researchers have identified specific genes that appear to influence migraine susceptibility. These genes are involved in immune response, oxidative stress, pain transmission, and mood, through their effects on:
- Tyrosine metabolism
- Calcitonin gene-related peptide
Specifically, there appears to be a connection between serotonin, genetic variants of the HCRTR1 gene, the polymorphism 5-HTTLPR, and hypocretin-1. Serotonin inhibits the activity of hypocretin neurons and seems to influence whether a migraineur experiences associated aura during an episode. (R) Serotonin also constricts nerve endings and blood vessels, which influences nociceptive pain. Low levels of serotonin would, therefore, dilate blood vessels and, potentially, trigger migraine.
Ovarian hormones also seem to influence levels of serotonin, which may go some way towards explaining why women experience migraines at a much higher rate than men. It may also offer a reason for the so-called “menstrual migraine.”
Ensuring a good intake of foods that support healthy serotonin synthesis seems sensible for migraineurs. This means getting enough of the amino acid tryptophan, which the body converts into serotonin, as well as cofactors in serotonin synthesis, such as vitamin B6.
Although it may seem counterintuitive at first, increasing protein consumption does not increase serotonin levels in the brain. This is because tryptophan is one of the least-abundant amino acids in food, and the other amino acids outcompete tryptophan for transport across the blood-brain barrier. For more on natural ways to increase serotonin levels, see John’s post on increasing serotonin with food and supplements.
Genetic variations associated with migraines
The first genetic studies of migraine focused on the rare subtype of migraine: familial hemiplegic migraine (FHM), or migraine with aura. FHM was first described in 1910 as affecting four generations of a family in the United Kingdom. The symptoms of FHM, during aura, include hemiparesis (weakness in half of the body), as well as temporary visual symptoms including blind spots (scotomas), zig-zagging lines, double vision, and flashing lights. FHM also tends to be associated with a longer aura than other types of migraine.
Early research involving families with FHM identified three causative genes: CACNA1A, ATP1A2 and SCNA1A. (R) These genes code for proteins that regulate ion transports across neuronal and glial cell membranes. Subsequent research has identified other genes that may be involved in FHM, including MTHFR, KCNK18, HCRTR1, SLC6A4, STX1A, GRIA1 and GRIA3. (R)
Five single-nucleotide polymorphisms (SNPs) have been identified as playing a role in migraine susceptibility in Western populations:
- rs4379368, in the succinic HMG coenzyme A transferase (C7orf10) gene
- rs10504861, near the matrix metallopeptidase 16 (MMP16) gene
- rs10915437, near the adherens junctions associated protein 1 (AJAP1) gene
- rs12134493, upstream of the tetraspanin 2 (TSPAN2) gene
- rs13208321, within the four and a half LIM domains protein 5 (FHL5) gene
These SNPs are not, however, associated with an overall increase in the incidence of migraine in Han Chinese or She Chinese peoples, although certain SNPs do appear to be strongly associated with certain types of migraine, i.e. migraine with aura (MA) and migraine without aura (MO). (R)
For instance, the CT genotype of rs4379368 was identified in one study in 75% of patients with MA, compared to just 47.9% of patients with MO, and 48.5% of non-migraineurs. And, the TT genotype of rs10504861 was found in 8.3% of patients with MA compared to 0.5% of controls, while the CC genotype of rs12134493 was less common in patients with MO (80.6%) than in controls (88%). (R)
In a study looking at She Chinese people with migraine, the rs4379368 T allele was found to be more common (58.7%) than the C allele, and CT and TT genotypes were more frequent in migraineurs than in the control groups, at 54.0% and 31.7%, compared to 48.0% and 28.7%, respectively. Sex differences were also observed in this study, with female migraineurs more likely to have the CT and TT genotypes compared to females without migraines, at 53.8% and 30.9%, compared to 46.7% and 27.6, respectively. The CC genotype of rs4379368 and AA or AG genotype of rs13208321 were associated with a reduced risk of migraine in this population. (R)
MTHFR mutations and severe migraines
Other genetic variations also are being investigated for their role in migraine pathology. These include mutations in the genes regulating MTHFR production and activity, with evidence to suggest that people with the ‘T’ allele of C667T experience more frequent and severe migraines. In one study, 20.3% of migraine sufferers had the homozygous transition (T/T) compared to just 9.6% of people without migraines. What’s more, the T/T variation was identified in a staggering 40.9% of people with migraine with aura. (R)
In a pilot study, migraineurs with a genetic variation affecting MTHFR activity were given supplements providing folate, vitamin B6, and vitamin B12 for six months. Their migraine symptoms improved, and this improvement corresponded with a decrease in homocysteine levels. (R)
Migraines and diet
In addition to the SNPs just mentioned, there is considerable evidence linking migraines and genetics via our food choices. (R) Indeed, several common foods, food additives, and beverages appear to be a migraine trigger in people with a genetic susceptibility to migraines. Conversely, other foodstuffs appear to protect against migraines in some people.
Some of the most common drinks and foods linked to migraines (R) include:
- Red wine, beer, and whisky distilled in copper stills
- Citrus fruits
- Tea and coffee
- Pork and cured or processed meats (such as hot dogs)
- Milk and dairy products
- Nuts and beans
- Cola drinks
There has been some speculation that these dietary components may trigger migraines as part of an immunologically based allergic reaction, leading to the suggestion that migraineurs eliminate potential dietary triggers. However, there is no clear evidence that migraineurs have higher levels of immunoglobulin-E (IgE) when encountering these foods, compared to non-migraineurs. What’s more, elimination diets pose a risk of widespread nutrient deficiencies that may themselves raise the risk of migraine.
See also: Understanding histamine intolerance
IgE is not the only immunoglobulin in question, though. There is some evidence that following a diet that eliminates foods that trigger an IgG response may help decrease migraine frequency and severity. This was seen in one study where participants followed such a diet for six weeks either before or after a provocation diet that included “trigger” foods, with a two-week diet-free period as a washout in between conditions. The exclusion diet was associated with significantly fewer headache days and migraine attacks, down from 10.5 days to 7.5 days, and from 9 to 6.2, respectively. Targeted dietary restriction, based on IgG testing, may, therefore, be useful for some migraineurs. (R)
Dietary migraine triggers
Current thinking on migraines suggests that certain substances in the foods and drinks mentioned above may modulate vascular tone or prompt other physiological effects that trigger migraines in those with a genetic susceptibility. (R) Such substances may include:
- Histamine (more on this below)
- Phenolic flavonoids
- Sulfites (more on this below)
- Food additives such as sodium nitrate, monosodium glutamate, and aspartame
- Caffeine (withdrawal)
One of the ways in which these substances appear to influence migraine attacks is by promoting the release of serotonin and norepinephrine, neurotransmitters that modulate vasoconstriction and vasodilation. These substances may also cause migraines through direct stimulation of the trigeminal ganglia, brainstem, and cortical neuronal pathways. (R) Hypoglycemia is another migraine trigger, meaning that migraineurs would do well to avoid fasting or skipping meals.
It’s also worth noting that what triggers a migraine one day may not trigger a migraine on any other given day. This is thought to be due, in part, to something called histamine load.
Histamine and migraines
Histamine is the immune system’s first line of defense, with immune system cells called leukocytes releasing histamine in response to a perceived invader. Histamine is a key neurotransmitter, but too much histamine can trigger symptoms including migraine.
The enzymes responsible for clearing histamine are called histamine N-methyltransferase (HNMT), which clears histamine in the cells, and Diamine Oxidase (DAO), which scavenges excess “free-floating” histamine.
The ability to clear histamine varies between individuals and depends on factors including our genes and nutritional status. Several genes have been identified as playing a role in histamine clearance. These include the AOC1 gene, where mutations can compromise DAO activity and reduce histamine clearance.
Alcohol, some foods, and certain medications (including antibiotics) can also interfere with DAO production and activity, while nutrients including vitamins C and B6, and copper, are cofactors in DAO production. As such, if you have an AOC1 or HNMT mutation, it’s wise to avoid those substances that inhibit DAO production and ensure a good intake of the nutritional cofactors needed for effective histamine clearance. If you suspect that histamine might be contributing to your migraines, you’ll want to read this post by John: Welcome to Austin, now lay off the sauerkraut.
Energy metabolism and migraines
In addition to the interaction between migraines, MTHFR, histamine, and homocysteine, some biochemical evidence suggests that migraineurs may suffer due to other forms of metabolic dysfunction. Elevated lactic acid levels have been noted in the blood and cerebrospinal fluid of migraineurs, for instance, with lactic acidosis characteristic of mitochondrial dysfunction. (R)
Preliminary research suggests that migraineurs may benefit, therefore, from supplements providing nutritional cofactors for mitochondrial metabolism. Such nutrients include coenzyme Q10, PQQ, magnesium, and B vitamins, as well as fatty acids and phospholipids. (R)(R)
Many migraineurs have also observed that the food preservative sulfite can trigger migraines. This isn’t all that surprising, given that sulfite impairs the Krebs cycle, potentially reducing production of adenosine triphosphate (ATP, the body’s main form of energy) by some 50%. Sulfite does this by inhibiting the conversion of glutamate by glutamate dehydrogenase into alpha-ketoglutarate, an important fuel source for the Krebs cycle. What’s more, our neurons seem to be especially vulnerable to a disruption in this energy cycle, so migraineurs would do well, it seems, to avoid sulfites where possible. (R)
In conclusion, the current body of evidence suggests that a variety of genetic variations play a role in your risk of migraine. Many of these mutations exert their effects via nutritional mechanisms, so if you suffer from migraines it seems smart to look to your genotype for clues as to how nutrigenomics could help prevent migraines or reduce symptom severity.
If you need help getting started, Aaron wrote an excellent post on the types of DNA tests out there and how to choose one that works for you: Finding the best DNA test: Should I genotype or sequence? After you receive your results, this blog, along with our Genetics and Nutrition Guide, are excellent resources to keep handy during the next steps of your health-improvement journey.
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