Caffeine sensitivity depends on your genes

Caffeine sensitivity depends on your genes

Pawel Malczewski
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Short summary

DNA plays a big part in how much coffee we can drink, to the point that some of us should avoid or at least reduce coffee or other caffeinated drinks.

There are a number of genes that determine how well we can take a caffeine hit, since they influence the rate of the breaking down of caffeine, sensitivity and tolerance to caffeine and also the rate of breaking down other harmful substances induced in the body by caffeine. For a quick answer click here.

Explanation

How we react to caffeine is dependent largely on genetics and varies between individuals.
There are a few genes responsible for how efficiently we deal with caffeine in our diet. (1)Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. Available here. (2)Josse AR, Da Costa LA, Campos H, El-Sohemy A. Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption. Am J Clin Nutr. 2012 Sep;96(3):665-71. Available here.

  1. Gene “CYP1A2” is responsible for releasing the liver enzyme called “polymorphic cytochrome P450 1A2 (CYP1A2) enzyme” which breaks down caffeine.
  2. Gene “AHR” which controls if gene CYP1A2 switched on or off.
  3. Gene “ADORA2A” controls sensitivity to caffeine.
  4. Gene “COMT” which controls the breakdown of catecholamines.

Please note that the studies of these genetic factors related to caffeine and catecholamine metabolism are very recent, so many previous studies that measured the effects of caffeine on our bodies did not consider these factors.

Caffeine Sensitivity

Gene CYP1A2 and the rate of breaking down caffeine
After drinking a cup of coffee, most of the caffeine gets absorbed by the body and circulates for a few hours while slowly degrading in our system. 95% of caffeine (along with some drugs and carcinogens) is broken down inside the liver using an enzyme called “polymorphic cytochrome P450 1A2 enzyme”. (3)Sachse C, Brockmöller J, Bauer S, Roots I. Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999 Apr;47(4):445-9. Available here. (4)Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here. How long the caffeine stays in the body is measured by the half-life of the substance. Half-life indicates how long it takes for half of the substance to be broken down and excreted from the body. The half-life of caffeine depends on several factors:

  • Levels of enzymes that break down caffeine;
  • Amount of ingested caffeine;
  • Liver and overall health;
  • What drugs or medications are taken at the time of caffeine intake;
  • Pregnancy.

The half-life of caffeine in healthy adults is about four hours. The gene CYP1A2 is responsible for releasing the enzyme that breaks down caffeine. It is not responsible, however, for the tolerance of caffeine.

There are two variations of this gene – one that helps metabolize caffeine faster and another that helps metabolize it slower.

Every person has two copies of this gene, one inherited from each parent.  A combination of two of the fast variant copies (fast+fast) will make you a fast caffeine metabolizer. Any other combinations (fast + slow) or (slow+slow) will make you a slow caffeine metabolizer.

Slow Metabolizers

  • Slow metabolizers have an increased risk of non-fatal heart attack when they drink daily 2-3 cups of coffee (200-300mg caffeine).
  • Slow metabolizers who drink 4 cups of coffee per day have 4 times the risk of heart attack comparing with those that drink about 1 cup (100mg caffeine) per day.
  • Women, who are slow metabolizers, are planning to get pregnant and consume 2-3 cups of coffee per day (200-300mg caffeine) increase the risk of infertility.
  • Pregnant women who are slow metabolizers and consume 2-3 cups of coffee per day (200-300mg caffeine) have an increased risk of miscarriage. (5)Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. Available here. (6)Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.

Fast Metabolizers
Fast metabolizers have shown a 22% lower risk of heart attack by having 2-3 cups of coffee per day (200-300mg caffeine). For more technical explanation please click here.

Gene AHR and switching on gene CYP1A2
The gene called AHR is another gene associated with the rate of caffeine breakdown. It does this indirectly by regulating gene CYP1A2. (7)Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, et al. Genome-Wide Meta-Analysis Identifies Regions on 7p21 (AHR) and 15q24 (CYP1A2) As Determinants of Habitual Caffeine Consumption. Plos Genetics. April 7, 2011. Available here.

Gene ADORA2A and sensitivity to caffeine
As mentioned above, caffeine attaches to the receptor A(2a). Gene ADORA2A variations are responsible for receptor A(2a) which is associated with caffeine sensitivity. (8)Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here. (9)Rétey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP. A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther. 2007 May;81(5):692-8. Epub 2007 Feb.28. Available here. (10)Rogers PJ, Hohoff C, Heatherley SV, Mullings EL, Maxfield PJ, Evershed RP, Deckert J, Nutt DJ. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology. 2010 Aug;35(9):1973-83. Available here.

Technically speaking, people who carry two copies of the C allele of ADORA2A are more sensitive to the effects of caffeine and suffer from sleep disturbances. People with two copies of the T allele of ADORA2A experience greater anxiety after caffeine. (11)Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.

Gene COMT and the breaking down of catecholamines
Caffeine increases the release of catecholamines. When in high concentrations, catecholamines damage cells in the muscular tissue of the heart leading to an increased risk of heart attack.An enzyme called Catechol-0-Methyl Transferase (COMT) breaks down catecholamines.

The less active that the COMT enzyme is, the bigger the concentration of catecholamines and the more probability of damage to the heart and a resulting increased risk of a heart attack.

The gene responsible for making this enzyme more active is the “COMT gene”. COMT has a number of variations. Therefore, if you have a COMT rs4680 variant, which causes low COMT activity, by drinking coffee you are increasing the risk of a heart attack. (12)Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here. (13)Happonen P, Voutilainen S, Tuomainen TP, Salonen JT. Catechol-O-Methyltransferase Gene Polymorphism Modifies the Effect of Coffee Intake on Incidence of Acute Coronary Events. Published: December 27, 2006. Available here. The risk of a heart attack grows if you are a slow metabolizer and have low COMT activity.

Receptor A1 and caffeine tolerance

Caffeine attaches to two receptors in the cells surface A(1) and A(2a). Drinking coffee or caffeinated beverages frequently is associated with increased tolerance to caffeine. This occurs since chronic caffeine intake increases the density (number) of receptors. The more receptors that get produced, the more we crave caffeine. (14)Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.

Conclusion

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People who drink coffee, other caffeinated drinks or products which may contain caffeine, such as chocolate, should be aware how their genes influence caffeine effects.
It is useful to figure out if you can drink coffee and what the upper limit is in order to avoid unpleasant side effects and potential health risks.

Here are some of the symptoms from people with caffeine sensitivity:

      • Jitteriness;
      • Increased heart beat;
      • Nausea;
      • Sweating;
      • Dizziness;
      • Diarrhea;
      • Insomnia;
      • Headache;

People who are sensitive to caffeine and those who cannot break down caffeine efficiently usually feel the effects after drinking one or two coffees. The safest option to make sure how you are handling caffeine is to do genetic tests.

References   [ + ]

1. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. Available here.
2. Josse AR, Da Costa LA, Campos H, El-Sohemy A. Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption. Am J Clin Nutr. 2012 Sep;96(3):665-71. Available here.
3. Sachse C, Brockmöller J, Bauer S, Roots I. Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999 Apr;47(4):445-9. Available here.
4. Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.
5. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. Available here.
6. Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.
7. Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, et al. Genome-Wide Meta-Analysis Identifies Regions on 7p21 (AHR) and 15q24 (CYP1A2) As Determinants of Habitual Caffeine Consumption. Plos Genetics. April 7, 2011. Available here.
8. Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.
9. Rétey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP. A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther. 2007 May;81(5):692-8. Epub 2007 Feb.28. Available here.
10. Rogers PJ, Hohoff C, Heatherley SV, Mullings EL, Maxfield PJ, Evershed RP, Deckert J, Nutt DJ. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology. 2010 Aug;35(9):1973-83. Available here.
11. Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.
12. Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.
13. Happonen P, Voutilainen S, Tuomainen TP, Salonen JT. Catechol-O-Methyltransferase Gene Polymorphism Modifies the Effect of Coffee Intake on Incidence of Acute Coronary Events. Published: December 27, 2006. Available here.
14. Yang A, Palmer AA, De Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (2010) 211:245-257. Available here.

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