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Gluten is a family of storage proteins found in various grains such as barley, rye, and wheat. Gluten is responsible for the soft and chewy texture of pastries and baked items. It also retains the moisture in bread, pasta, and cereal.  

Gluten intolerance and gluten sensitivity are two terms used interchangeably to describe a condition where the body recognizes gluten as an ‘enemy’ and initiates an immune response against it. 

Table of Contents

  1. Knowing the difference between gluten intolerance and celiac disease.
  2. What are the symptoms of gluten sensitivity?
  3. Is avoiding carbs to avoid gluten the best idea?
  4. Evolutionary significance: How did our ancestors respond to gluten?
  5. Gluten sensitivity among different ethnic groups.
  6. The genetics behind gluten sensitivity
    1. The HLA gene
    2. Non-genetic factors affecting gluten sensitivity
  7. Why get tested for gluten sensitivity?
  8. How to know if you are gluten-sensitive?
  9. Dietary recommendations to manage gluten sensitivity.
    1. Gluten-free foods
  10. Summary
  11. References

Knowing The Difference Between Gluten Intolerance And Celiac Disease

Gluten intolerance is also known as ‘non-celiac’ gluten sensitivity. 

Celiac disease is an exaggerated form of gluten intolerance. Upon consuming gluten, the immune system attacks the lining of the intestines. When the symptoms are more severe, the recovery is a lot harder.

Here, the body’s immune system, which is meant to protect it, mistakenly acts against it. This is known as an auto-immune response, which can be due to genetic reasons.

Since intestines play a big role in the absorption of essential nutrients, attacks on them over time can result in poor absorption of nutrients, putting you at risk for various deficiencies. When the gluten intolerance is non-celiac, the immune responses triggered do not damage the intestines but instead contribute to milder symptoms.

Gluten sensitivity symptoms are not restricted to just the digestive system. 

What are the symptoms of gluten sensitivity?

  1. Abdominal pain
  2. Diarrhea
  3. Bloating
  4. Constipation
  5. Nausea
  6. Headaches
  7. Fatigue
  8. Skin rashes
  9. Anxiety
  10. Depression
  11. Joint and muscle pain
  12. Numbness

Why Avoiding Carbs To Avoid Gluten May Not Be The Best Idea

All the fad about gluten-free diets has portrayed gluten-containing products, mainly wheat, in a bad light. While gluten is a big no-no for the gluten-sensitive, reduced consumption of whole grains may negatively impact your health. 

Whole grains like wheat, bran, and rye are rich sources of fiber. They also contain carbohydrates, proteins, and small amounts of B vitamins and minerals. 

Thus, avoiding gluten in the absence of an intolerance/sensitivity can end up being detrimental to your health.

Evolutionary Significance: How did our ancestors respond to gluten sensitivity?

Diana Gitig, a Ph. D. graduate from Cornell University, Massachusetts, mentions that celiac disease's first reported case dates back to 100 A.D. It was diagnosed by a Greek doctor, Aretaeus. Yet, the cause of the disease was never understood clearly. 

During the Dutch famine in the 1940s, when celiac patients received very little flour (wheat) for consumption, their symptoms started improving.

When fresh supplies of bread were reintroduced, the symptoms started worsening again. This was when wheat was isolated as the cause of the intestinal symptoms. 

Until the 1950s, only 1 out of 8000 were sensitive to gluten. Today, as high as 1 in every 100 individuals are gluten sensitive . 

Prof. David Sanders from the University of Sheffield takes help from the concept of evolution to answer this huge rise in cases. He claims that humans started eating wheat only recently, about 10,000 years ago. This is a very brief period considering that humans have walked on the planet for more than 2 million years. 

Humans initially consumed raw food, such as plants, fruits, and meat. Processed food (wheat, rye, and other grains), are relatively new in the evolutionary timeline. Prof. David acknowledges this fact and states that our body is still in the process of adapting, especially the food that contains gluten in it. With millions of years of having a gluten-free diet, it makes sense as to why gluten is considered a foreign body by our immune system.

Ethnicity And Gluten Sensitivity

Although a global analysis of gluten intolerance is yet to be done, a nationwide study was conducted in the United States. Over 400,000 biopsy results were examined to understand if ethnicity played a role in gluten intolerance and celiac disease. The following results were concluded after the study : 

It is also worth mentioning that gender studies showed that both men and women had equal chances of being gluten-sensitive. Hence it can be inferred that gender does not play a role in this intolerance.

Genetics And Gluten Sensitivity

The HLA gene

The Human Leukocyte Antigen (HLA) gene system plays a role in the production of the Major Histocompatibility Complex (MHC), which are proteins present on the cell surfaces. They play a role in regulating the immune system

Two classes of the HLA gene known as HLA-DQ2 (HLA-DQ2.2 and HLA-DQ2.5) and HLA-DQ8 are linked with gluten intolerance risk. 

Four types of the HLA gene, HLA DQ, HLA DQ 2.5, HLA DQ 2.2 (has three sub-types), and HLA DQ7, have been linked to gluten intolerance.

In a study conducted to assess the genetic influence on gluten intolerance, nearly all the patients with celiac disease had the risk allele in the HLA DQ2 and the HLA DQ8 genes. The absence of the same was found in 100% of people without celiac disease. In another study conducted to analyze the HLA gene types, people with the C allele in HLA DQ8, T allele in HLA DQ 2.5, the T, C and A alleles in different subtypes of HLA DQ 2.2 (M1, M2, and M3 respectively), and A allele in HLA DQ7 were shown to have an increased risk of reacting to gluten in their diets.

Non-Genetic Causes Of Gluten Sensitivity

Some of the non-genetic causes of gluten sensitivity are:

Not all people are born with gluten sensitivity. It is possible to acquire it during the course of life. This intolerance can be triggered after surgery, childbirth, or after a period of severe stress.

Commonly Associated Conditions With Gluten Sensitivity

Gluten Sensitivity Can Affect Hormone Levels

Gluten sensitivity increases the risk of an adrenal hormone imbalance.

The adrenal glands pick up on the stress levels.

Unstable sugar levels and inflammation of the digestive tract resulting from gluten intolerance cause the adrenal glands to secrete cortisol.

This leads to an increase in body fat, fatigue, and irritable mood.

Gluten Sensitivity Can Increase Fatigue

Fatigue is one of the most common symptoms of celiac disease and non-celiac gluten sensitivity.

In fact, fatigue and tiredness are the symptoms that last longest, even after the individual has shifted to a gluten-free diet.

Fatigue in gluten intolerant individuals occurs due to two main reasons:

  1. The inflammation in the digestive system results in improper absorption of nutrition, leaving the body deficient in certain nutrients.
  2. Gluten-allergy or sensitivity leads to diarrhea, characterized by loose, watery stools. This leads to lots of water and nutrients elimination from the body.

Dehydration is also a major cause of fatigue and tiredness in gluten intolerant people.

Gluten Sensitivity Can Cause Neurological Symptoms

Patients suffering from celiac and non-celiac forms of gluten intolerance have reported neurological symptoms such as headaches, brain fog, anxiety, depression, and peripheral neuropathy.

Gluten can also cause other disorders like insomnia, migraines, ADHD, epilepsy, schizophrenia, bipolar disorder, and in a minute number of cases, gluten ataxia (antibodies directed at gluten attacks the brain).

Gluten Sensitivity Can Cause Mood Disorders

Many studies have shown a correlation between gluten intolerance and depression, anxiety, and other neurological syndromes.

A study conducted by Christine Zioudrou and her colleagues at the National Institute of Mental Health in 1979 found that some gluten compounds can attach to the morphine receptors in the brain.

The morphine that is produced in the body is known as endorphins. These are released in our body for various reasons, for instance, to reduce/manage pain.

Certain compounds of gluten (exorphins) mimic the structure of endorphins and attach to the receptors. 

Thus, the endorphins have no place to attach to and are not activated. This can lead to mood-related disorders like depression and anxiety. 

Gluten Sensitivity Can Cause Insomnia

A large majority of the people who suffer from gluten-intolerance report lack of sleep and poor sleep quality.

Due to digestive symptoms, neurological symptoms, and generalized fatigue and tiredness, most people suffer from a lack of sleep or other related conditions.

How To Know If You Are Gluten Sensitive

If you think you have some of the symptoms of gluten sensitivity, talk to your doctor before jumping to any conclusions. The doctor can run tests and review your history to help reach a diagnosis.

Another way to find out if you have a risk for gluten allergy is to do a genetic test. If you already have your DNA raw data from any ancestry company like 23andMe, Ancestry DNA, Family Tree DNA or whole genome data, you can upload it to Xcode Life for a Gene Nutrition report.

In the Gene Nutrition report you can find an in-depth analysis of your genetic variants for gluten sensitivity and ways to manage or prevent it.

Dietary Recommendations For Gluten-Sensitive Individuals

A gluten-free diet seems pretty straightforward - just removing gluten from your diet. But completely avoiding gluten can be challenging as many ingredients added to food like soy sauce, mayonnaise, and roasted nuts also contain gluten. 

Whole grains like wheat and barley are well-known harbourers of gluten. So wheat-based bread, pasta, or baked goods should be avoided. 

What are the naturally gluten-free foods? 


  1. Gluten gluten sensitivity is a condition where the body recognizes gluten as an ‘enemy’ and initiates an immune response against it. 
  2. Celiac disease is an exaggerated form of gluten sensitivity.
  3. Evolutionarily, gluten could be considered foreign by the immune system since humans have gone millions of on a gluten-free diet.
  4. Studies have shown that individuals with with celiac disease had risk variants in the HLA DQ2 and the HLA DQ8 genes. Check you DNA raw data to know whether you have the risk variants.
  5. The absence of the same was found in 100% of people without celiac disease.
  6. Non-genetic causes of gluten sensitivity: gastrointestinal infections and abnormal gut bacteria.
  7. Conditions associated with gluten sensitivity: hormonal imbalance, depression, fatigue and insomnia.
  8. Genetic analysis is good way to prevent and manage gluten sensitivity effectively.
  9. You can use your 23andMe, AncestryDNA, Family Tree DNA, or whole genome data to check if you have the risk variants for gluten sensitivity.



What does the CYP1A2 gene do? 

CYP1A2 codes for the production of 21-hydroxylase, which is part of the cytochrome P450 family of enzymes.

This family of enzymes is quite important as it is a part of many processes, that include breaking down drugs, production of cholesterol, hormones, and fats.

The adrenal glands secrete the enzyme, 21-hydroxylase.

Situated on the top of the kidneys, the adrenal glands also produce hormones like epinephrine and cortisol.

Incidentally, 21-hydroxylase plays a role in the production of cortisol and another hormone named aldosterone.

Cortisol is a stress-related hormone and plays a role in protecting the body from stress, as well as reducing inflammation.

Cortisol also helps in maintaining blood sugar levels.

Aldosterone, also known as the salt-retaining hormone, regulates the amount of salt retained in the kidneys.

This has a direct consequence on blood pressure, as well as fluid retention in the body. 

There seems to be an interesting trend in the activity of the CYP1A2 gene and caffeine intake.

The consequence of being a “rapid” or a “slow” metabolizer of caffeine can have effects on an individual’s cardiovascular health.

This article explains the wide-ranging effects of this gene, caffeine intake,  cardiovascular health, hypertension, and even pregnancy!

What is the association between CYP1A2 and caffeine metabolism?

In the body, CYP1A2 accounts for around 95% of caffeine metabolism.

The enzyme efficiency varies between individuals.

A homozygous, that is, AA genotype represents individuals that can rapidly metabolize caffeine.

Some individuals have a mutation in this locus and thus have the AC genotype.

These individuals are “slow” caffeine metabolizers.

CYP1A2 and cardiovascular health

There seems to be a link between CYP1A2, the incidence of myocardial infarction (MI), and coffee intake.

The positive effects of coffee include lowering a feeling of tiredness and increasing alertness; however, it can also narrow the blood vessels.

This increases blood pressure and could lead to cardiovascular disease risk.

Rapid metabolizers of coffee have the AA genotype and may unravel the protective effects of caffeine in the system.

However, the individuals that are slow metabolizers have a higher risk of MI.

This suggests that the intake of caffeine has some role in this association. 

Yet another study associated DNA damage due to mutagens found in tobacco smoking could contribute to MI.

The study included participants who were genotyped at the CYP1A2 gene.

They found a group of ‘highly inducible’ subjects that had a CYP1A2*1A/*1A genotype.

These individuals have a greater risk for MI, independent of their smoking status.

This also means that there is some intermediary substrate that the CYP1A2 gene decomposes, and if this gene has a mutation, it could lead to a higher risk of MI. 

In a study conducted on 2014 people, people who were slow metabolizers of caffeine (C variant) and who consumed more than 3 cups of coffee per day had an association with increased risk for myocardial infarction. 

In a similar study on 513 people, increased intake of coffee, among slow metabolizers, has an association with an increased risk for hypertension.

The association between smoking and hypertension

Smoking is capable of inducing the CYP1A2 enzyme. Smokers exhibit increased activity of this enzyme.

In a study conducted on 16719 people, people with the A variant, and who were non-smokers, were 35% less likely to be hypertensive than people with the C variant.

In the same study, CYP1A2 activity had a negative association with blood pressure among ex-smokers.

But for people who were still smoking, the same gene expressed an association with increased blood pressure.

The gene CYP1A2 also has an association with caffeine metabolism and smoking.

A study aimed to tie these concepts together to find the relationship between this gene and blood pressure (BP).

The main measurements of the study were caffeine intake, BP, and the activity of the CYP1A2 gene.

In non-smokers, CYP1A2 variants (having either a CC, AC, or AA genotype) were associated with hypertension.

Higher CYP1A2 activity was associated with people who quit smoking and had lower BP compared to the rest but had a higher BP while smoking.

In non-smokers, CYP1A2 variants (having either a CC, AC or AA genotype) were associated with high caffeine intake, and also had low BP.

This means that caffeine intake plays some role in protecting non-smokers from hypertension, by inducing CYP1A2.

The effect of the CYP1A2 on pregnancy and caffeine intake

The intake of caffeine during pregnancy has an association with the risk of reduced fetal growth.

High caffeine intake shows a link to decreased birth weight.

The babies are also at risk of being too small during the time of pregnancy.

This was also observed in a study conducted on 415 Japanese women.

Women with the A variant who drank more than 300 mg of coffee per day were shown to be at an increased risk of giving birth to babies with low birth weight.


In conclusion, there are a lot of effects that the CYP1A2 gene has on the body. Many studies, as noted above, seem to link the activity of this gene to caffeine intake.

A variant at the CYP1A2 gene can determine whether an individual is a fast or slow metabolizer of caffeine, and this has some effect on the blood pressure and cardiovascular health of an individual.

The gene also plays a role in regulating an infant’s weight during the pregnancy of a woman,  and this has a link with caffeine intake. It is thus interesting to analyze the effect of the variants of the CYP1A2 gene on an individual, based on their caffeine intake. 



Do you have your DNA raw data from 23andMe, AncestryDNA, FTDNA, LivingDNA, etc.?

Upload it to Xcode Life to know about your CYP1A2 caffeine metabolism and caffeine sensitivity variants.

Published on 18 June, 2020

It is hard to believe that caffeine, a stimulant that holds popularity in battling fatigue and improving creativity, can do any harm.

1. Caffeine Sensitivity

Caffeine sensitivity is a term that describes the efficiency of the human body to process caffeine and to metabolize it.

We have all heard of co-workers who drink 6 cups of coffee, the recreational drink for nearly 60% of Americans, every day, and friends who guzzle a cup an hour before bedtime.

Yet there are some of us who feel jittery, anxious, or even restless after a single cup.

So, is caffeine a scourge, a tonic, or a mix of both?

Is coffee good for you?

For starters, coffee has a few benefits.

A large research study showed that Americans get more antioxidants from coffee than from any other dietary source.

Other studies have shown that there are several nutrients in a cup of brewed coffee, like Magnesium, Niacin, and Potassium, depending on the soil nutrients and the type of processing.

2. How caffeine works

Adenosine is an organic compound that inhibits arousal and promotes sleepiness upon binding to its receptor.

Caffeine has a structure similar to adenosine and works as an adenosine receptor antagonist.

It competes with adenosine to bind to the adenosine receptor.

This process promotes wakefulness.

Though this can affect the quality of sleep among certain people, it could help in situations like driving at night or averting jet lag, where mental alertness is critical.

Analyze Your Genetic Variants For Caffeine Sensitivity

According to the U.S. Food and Drug Administration (FDA), 300 milligrams of caffeine are consumed every day by the average American. The Mayo Clinic states that drinking up to 400 milligrams per day is safe, which is approximately 4 cups.

A good cup of coffee is the most popular caffeine delivery mechanism that comes with a few health benefits like being a good source of antioxidants, warding off liver disease, and protecting against Parkinson’s.

The health risks and benefits have been understood, over the years, however, caffeine and metabolism, or the way in which our body processes the chemical, varies on several key factors.

3. Caffeine content in popular beverages

BeverageCaffeine content (mg)
Coffee8 oz cup - 95 mg
Espresso1 oz shot - 63 mg
Green tea8 oz cup - 28 mg
Black tea8 oz cup - 26 mg
Energy drinks8 oz cup - 91 mg
Sodas (Cola)16 oz cans - 49 mg
Coffee liqueur1.5 oz shot - 14 mg
Dark chocolate1 oz square 24 mg

4. Caffeine Metabolism: What CYP1A2 gene says

Caffeine, an alkaloid, is also known as  1,3,7-trimetilksantin.

It is acidic in its pure crystalline form and is found in over 60 plant species.

The enzyme CYP1A2 is responsible for the metabolism of caffeine in the liver.

Due to potentially ineffective CYP1A2 enzyme activity, some people can experience issues like caffeine jitters after 2-3 cups of coffee per day.

Such slower metabolizers of caffeine may experience problems with blood pressure, headaches, etc.

Learn More

<strong>Coffee and <em>CYP1A2</em>: 3 ways high caffeine intake can affect you!</strong>

5. More about the CYP1A2 gene

The CYP1A2 gene regulates the synthesis of the enzyme, and small variations in this gene have an association with the efficiency of caffeine metabolism.

Some people have a genetic predisposition to produce very little of CYP1A2 enzyme while others may produce a large amount.

Approximately 10% of the population is found to be rapid caffeine metabolizers, which rates them high on caffeine sensitivity.

Analyze Your Genetic Variants For Caffeine Sensitivity

Approximately 10% of the population are found to be rapid caffeine metabolizers, which rates them high on caffeine sensitivity.

6. Slow metabolizer variant

The polymorphism associated with caffeine metabolism is rs762551.

Studies have shown that individuals with AC or CC genotypes are slow metabolizers of caffeine.

These individuals have a high caffeine sensitivity.

They tend to have a slightly increased risk for heart attack upon consumption of more than 2 cups of coffee every day.

7. Rapid metabolizer variant

Individuals who have the A.A. genotype in the specific polymorphism of the CYP1A2 gene may be fast metabolizers.

These individuals have a low caffeine sensitivity.

study conducted on 553 individuals found that people with this genotype had a 70% reduction in the risk of a heart attack on increased caffeine consumption.

8. How many cups of coffee should you consume? Genetic testing for Caffeine metabolism

The polymorphism in the CYP1A2 gene is well studied and is useful to determine the caffeine metabolism status.

This, in turn, can shine some light on the tendency to consume caffeine. 

9. 23andMe caffeine results

The 23andMe reports provide caffeine metabolizer status.

There are other well known 23andMe third-party tools, like Xcode Life, that can provide a better understanding.

Upload your 23andMe raw data to find out your caffeine metabolism status.

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23andMe DNA raw data is the genetic information obtained after a genetic test, and it is usually provided as a text file.

This information can be downloaded after utilizing the 23andMe login provided to all 23andMe customers.

10. Using your Ancestry DNA raw data to identify your caffeine metabolizer status

There is a wealth of information provided by ancestry DNA that can be used to identify a number of health and nutrition-based traits.

Use your ancestry DNA login to download your Ancestry DNA raw data.

You can then upload your Ancestry DNA raw data onto our site to identify the caffeine metabolizer status.

11. 23andme vs. AncestryDNA vs. Xcode Life

23andme vs. AncestryDNA vs. Xcode Life pertaining to caffeine metabolizer status

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12. Your genetic predisposition to consume caffeine

People of certain genetic types tend to have a genetic predisposition to drink more cups of coffee.

Identification of this tendency will help in moderating coffee consumption, taking into account the caffeine metabolism status of the individual.

Genetic tests can help identify such parameters.

After all, it would be good to know if you are prone to guzzling down a little too much, especially when your caffeine sensitivity scale is tipped at the wrong end.

Updated on 10 June, 2020

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