General Information

An estimated 90% of all adults consume caffeine daily through food, beverage, and supplements. Our dependence on it has become something of a running cultural joke but is also a sign of certain intrinsic realities. As little as 100 mg a day, the amount in an average cup of coffee, is enough to foster caffeine addiction in some people (1).

But not every person joins the cult of caffeine after a few cups of coffee. We each respond differently to caffeine based on our genetic makeup. Some of us need to stop just short of mainlining coffee to feel its effects while others are still jittery hours after a cup of espresso in the morning. This range of reactions can largely be attributed to differences in how efficiently we metabolize caffeine and variations in the genes that control that metabolism. Our caffeine metabolism may also have more serious health implications due to the way it impacts our risk for cardiovascular disease.

Genetics of Caffeine Consumption

Several genes are involved in eliciting the different responses to caffeine among individuals. One is the CYP1A2 gene that encodes for a liver enzyme critical for the metabolism of caffeine. Another is the AHR gene, which controls when and how the CYP1A2 gene is switched on and off (2).

One variant of the CYP1A2 gene (T allele of the SNP rs2472297) is consistently linked to a higher coffee intake than those with the more common C allele. About 10% of the general population carries the T variant of this gene (Table 1). Unsurprisingly then, approximately 25% of people of European ancestry have this T variant, where coffee consumption is highest, per capita (3).

People who consume over 400 mg of caffeine, the equivalent of 4 cups of coffee, per day are also more likely to be carriers of a variant of the AHR gene (C allele of the SNP rs4410790, Table 1). About 49% of the general population carries the C allele of AHR. Scientists believe that the C allele increases the AHR protein’s activity in switching CYP1A2 on (4).

Table 1. Allele distribution of CYP1A2, AHR, and ADORA2A genes in major populations.

Gene/SNP Allele Africans Asians Caucasians CYP1A2; rs2472297 T

C 2%

98% 0%

100% 23%

77% CYP1A2; rs762551 A

C 56%

44% 67%

33% 68%

32% AHR; rs4410790 T

C 53%

47% 63%

37% 37%

63% ADORA2A;

rs5751876 T

C 66%

34% 49%

51% 39%

61%

Caffeine functions through adenosine A 1 and A 2a receptors on the cell surface; these two receptors have partially opposing effects. Animal studies have shown that chronic intake of caffeine increases the density of A 1 receptors, which are believed to be responsible for caffeine tolerance. In contrast, a variation in the gene ADORA2A, encoding for A2a, is associated with sensitivity to caffeine. Specifically, individuals carrying two copies of the C allele at rs5751876 of this gene (Table 1) are more sensitive to caffeine than those carrying two copies of the T allele(5). Those with the T allele are more likely to experience anxiety after consuming caffeine.

Caffeine metabolism is also associated with the risk for cardiovascular disease. A study published in 2006 in the Journal of the American Medical Association (JAMA) demonstrated that, ”slow” metabolizers of caffeine are at an elevated risk of suffering a heart attack if they consume 2 or more cups of coffee. While those who are “fast” metabolizers actually have reduced risk of a heart attack if they consume at least one cup of coffee per day compared to not consuming any coffee. A subsequent study by an independent group of researchers found similar findings with hypertension. People with the AA genotype at rs762551 (within the CYP1A2 gene) are “fast metabolizers” while those with the AC or CC are “slow metabolizers.” (6 and 7).

Variations in the genes responsible for caffeine metabolism also affect how you respond to certain medicines. For example, variants in the CYP1A2 gene that affect the enzyme’s efficiency affect the breakdown of certain drugs. For example, people with the so-called fast metabolizer gene are more resistant to drug therapies (clozapine) for schizophrenia (8).

1. Griffiths, R.R., Juliano, L.M., Chausmer, A.L. (2003). Caffeine pharmacology and clinical effects. In: Graham A.W., Schultz T.K., Mayo-Smith M.F., Ries R.K. & Wilford, B.B. (eds.) Principles of Addiction Medicine, Third Edition (pp. 193-224).

2. Josse AR, Da Costa LA, Campos H, El-Sohemy A (2012). Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption, American Journal of Clinical Nutrition, 96(3):665-71.

3. Sulem P, Gudbjartsson DF, Geller F, Prokopenko I, Feenstra B, Aben KK, Franke B, den Heijer M, Kovacs P, Stumvoll M, Mägi R, Yanek LR, Becker LC, Boyd HA, Stacey SN, Walters GB, Jonasdottir A, Thorleifsson G, Holm H, Gudjonsson SA, Rafnar T, Björnsdottir G, Becker DM, Melbye M, Kong A, Tönjes A, Thorgeirsson T, Thorsteinsdottir U, Kiemeney LA, Stefansson K (2011). Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption, Hum Mol Genet. May 15;20(10):2071-7.

4. Renda G, Zimarino M, Antonucci I, Tatasciore A, Ruggieri B, Bucciarelli T, Prontera T, Stuppia L, De Caterina R (2012). Genetic determinants of blood pressure responses to caffeine drinking, The American Journal of Clinical Nutrition, 95(1):241-8.

5. Yang A, Palmer AA, de Wit H (2010) Genetics of caffeine consumption and responses to caffeine, Psychopharmacology, 211(3):245-57

6. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H (2006). Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction, Journal of American Medical Association, 295(10):1135-41.

7. Palatini P, Ceolotto G, Ragazzo F, Dorigatti F, Saladini F, Papparella I, Mos L, Zanata G, Santonastaso M (2009). CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension. J Hypertension. Aug;27(8):1594-601.

8. Ozdemir V, Kalow W, Okey AB, Lam MS, Albers LJ, Reist C, Fourie J, Posner P, Collins EJ, Roy R (2001). Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C-->A polymorphism in intron 1 of the CYP1A2 gene: effect of grapefruit juice and low-dose fluvoxamine. J Clin Psychopharmacol. Dec;21(6):603-7.