Caffeine: Your Friend or Foe? (CYP1A2)

Caffeine, the world's most widely consumed psychoactive drug, boosts mood and energy levels, increases focus, and improves athletic performance. But while some people can drink lots of coffee at any given time of day and not be affected by it, others get jittery and nervous and can suffer from increased blood pressure and, potentially, heart disease. One of the genes responsible for these differences is CYP1A2.

In this post, we will look into the CYP1A2 gene and its effect on how your body reacts to caffeine. In particular, we will focus on how caffeine can either increase or decrease your risk of high blood pressure and heart disease based on your CYP1A2 genotype.

Before we dive in, however, we must note that CYP1A2 has several important functions and breaking down caffeine is only one of them. In addition, while this gene is central to caffeine metabolism, several other genes also affect the way you react to this substance. We will cover these in some of our future posts.

Depending on your CYP1A2 genotype, caffeine can either increase or decrease your risk of high blood pressure and heart disease.

CYP1A2 is an important detox enzyme that breaks down toxic chemicals, drugs, hormones, and other products of metabolism in order to eliminate them from your body. It's found mainly in the liver [R, R].

CYP1A2 metabolizes:

• Caffeine [R]
• Hormones: melatonin and estrogens (estrone and estradiol) [R]
• Metabolic waste products, such as bilirubin, and uroporphyrinogen [R]
• Toxins, such as aromatic heterocyclic amines (in cigarette smoke, charbroiled meat), polycyclic aromatic hydrocarbons (in cigarette smoke, diesel exhaust, pollution), and aflatoxin B1 (in contaminated food) [R]
• Drugs: theophylline, tacrine, atypical antipsychotics, Tylenol (acetaminophen), and MDMA (ecstasy) [R, R, R]

CYP1A2 is the main caffeine-metabolizing enzyme. Your genetic variants may determine up to 75% of CYP1A2 enzyme activity, while food, supplements, and smoking are responsible for the rest [R, R].

CYP1A2 breaks down toxins, drugs, hormones, and metabolic waste products. It is the main enzyme that breaks down caffeine.

One of the best-studied SNPs in the CYP1A2 gene is rs762551 (also known as -163C>A or CYP1A2*1F). It affects the activity of the enzyme and thereby determines how your body will react to the caffeine in a cup of coffee.

There are two possible variants (alleles): 'A' and 'C'. Baseline levels of the enzyme may be similar between the two, but 'A' is associated with higher "inducibility", which means the enzyme becomes more active in the presence of inducers such as caffeine or cigarette smoke [R, R, R].

You can see your genotype for this SNP in the table below:

CYP1A2 rs762551

• ‘AA’  (0.57): "Fast metabolizer", breaks down caffeine quicker, caffeine has less effect on the body 
• ‘AC’  (1.67): "Slow metabolizer", breaks down caffeine slower, caffeine has more effect on the body
• ‘CC’    (1.67):  "Slow metabolizer", breaks down caffeine slower, caffeine has more effect on the body

If your genotype is 'AA', your body processes caffeine and other substances metabolized by this gene much more quickly (when induced), and these substances will have less of an effect on your body.

If your genotype is 'AC' or 'CC', you process caffeine and other substances metabolized by the CYP1A2 enzyme more slowly, and they have more of an effect on your body.

The same amount of caffeine will therefore tend to have more negative effects on CYP1A2 slow metabolizers than on fast metabolizers! About 59% of people are slow caffeine metabolizers.

People with 'AA' genotype or "Fast Metabolizers" process caffeine more quickly. Those with 'AC' and 'CC' genotypes or "Slow Metabolizers" process caffeine more slowly, i.e. it stays active in their bodies for longer.

Fast Metabolizers

If you are a fast metabolizer (with an ‘AA’ genotype), you are unlikely to get nervous or anxious after drinking coffee [R]. You are also more likely to benefit from caffeine as an athletic performance booster [R]!

But more importantly, drinking coffee may actually protect you against developing high blood pressure (hypertension) and heart disease [R, R].

In one study, people with this genotype who drank 2-3 cups of coffee per day (moderate drinkers) were 20% less likely to develop high blood pressure than fast metabolizers who didn’t drink coffee. Meanwhile, the risk for heavy drinkers (more than 3 cups per day) was 64% lower [R]!

Similarly, in another study, fast metabolizers younger than 60 had a lower risk of heart attack than fast metabolizers who didn’t drink coffee [R]:

• 52% lower when drinking 1 cup/day
• 43% lower when drinking 2-3 cups/day
• 17% lower when drinking 4 or more cups/day

This protective effect somewhat decreased in people over 60 [R].

Slow Metabolizers (AC and CC genotype)

If you are a slow metabolizer, you can get nervous and anxious after drinking coffee or other caffeine-containing products [R]. You are also less likely to benefit from caffeine when it comes to exercise—in fact, it may even reduce your athletic performance [R]!

In addition, drinking coffee regularly can increase your risk of developing high blood pressure (hypertension) and heart disease [R, R].

People with this genotype who drink 2-3 cups of coffee per day have a 72% higher risk of high blood pressure than slow metabolizers who don’t drink coffee. Moreover, heavy drinkers who drink more than 3 cups/day are 3 times more likely to develop high blood pressure (200% higher risk) [R]! 

In addition, slow metabolizers younger than 60 who drink coffee have a higher risk of heart attack by [R]:

• 24% when drinking 1 cup/day
• 67% when drinking 2-3 cups/day
• 133% when drinking 4 or more cups/day

The risk is not as high for people over 60 [R].

The good news is that coffee can protect women with this genotype against breast cancer. In particular, CYP1A2 slow metabolizer women who are carriers of the BRCA1 mutation have a 64% lower risk of breast cancer if they drank coffee in their youth, compared to similar women who never drank coffee [R, R].

Caffeine protects people with the ‘AA’ genotype against high blood pressure and heart disease, and it may boost their athletic performance. People with at least one ‘C’ allele experience the opposite effect.

Caffeine, Blood Pressure, and Heart Disease

We know that caffeine stimulates the sympathetic (fight-or-flight) response, which is one of the mechanisms by which caffeine raises blood pressure and may increase the risk of heart disease. This effect is much greater in slow metabolizers ('C' carriers) [R]. 

In fast metabolizers ('AA' genotype), caffeine's effect on blood pressure seems to be negligible and outweighed by the blood-pressure-lowering action of polyphenols and other bio-active compounds in coffee [R].

Caffeine & Athletic Performance

If coffee has more of an effect on slow metabolizers, shouldn't it boost their athletic performance more?

There is a theory that explains why this is not the case. We know that coffee narrows the blood vessels. In 'C' carriers, this effect is active for longer, potentially reducing how much oxygen and nutrients are delivered to the muscles during exercise [R].

Additionally, when caffeine is broken down, you get theobromine, theophylline, and paraxanthine: performance-enhancers themselves. Slow metabolizers need more time to produce these substances [R].