Oct 10, 2023
Caffeine, a xanthine alkaloid compound, is widely consumed by humans as it is present in many normal beverages such as tea, coffee, soda drinks, and some medications. Acting as a potent central nervous system stimulant, it triggers arousal and alertness, improves mood, and causes the release of catecholamines that cause beneficial effects on human behavior. Caffeine is absorbed by the stomach and small intestine within 45 minutes (Barcelos, R. P. et al., 2020). Caffeine is almost completely metabolized via CYP1A2 to paraxatin (82%), theobromine (11%), and theophylline (5%). Caffeine can have many negative effects on the body, such as tachycardia, tremors and flushing. These adverse effects are affected by CYP1A2 activity, gender, and smoking. Health effects such as decreased bone mineral density, reduced risk of hormone-related cancer in women, protection against Parkinson's disease, and development of diabetes have been associated with coffee intake (Rodenburg, E. M. et al., 2012).
What is the ADORA2A Gene?
Adenosine A2A receptors (A2A Rs) mediate the effects of extracellular adenosine. A 2A Rs control glial function and brain metabolic adaptation and play a role in different psychiatric disorders, especially mood disorders and anxiety (Childs, E., et al., 2008). The primary mechanism by which caffeine produces its central effects is by blocking adenosine receptors. At physiologically relevant concentrations, caffeine binds with high affinity to adenosine A1 and A2A receptors, antagonizing the effects of endogenous adenosine. Therefore, some people are sensitive to the anxiogenic effects of caffeine, as functional changes in these receptors caused by genetic variation can alter the responses to caffeine (Alsene K. et al., 2003).
What is the CYP1A2 Gene?
The cytochrome P450 enzyme CYP1A2 participates in the metabolism of many commonly used drugs, including clozapine, imipramine, caffeine, paracetamol, phenacetin, theophylline, and some neurotoxins, and activates many procarcinogens (Sachse, C. et al., 1999). Therefore, any change in CYP1A2 activity affects drug metabolism, altering the risk of developing cancer and other diseases. CYP1A2 activity varies widely between individuals, and a number of environmental and genetic factors have been reported to contribute to these variations. A number of drugs, including oral contraceptives, have been reported to induce or inhibit CYP1A2. In addition, some habits such as smoking also affect enzyme activity, and this effect appears to be related to CYP1A2 polymorphism (Djordjevic N. et al., 2010).
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CAFFEINE SENSITIVITY |
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Genes |
rs |
Minor Allele |
Minor Allele Description |
Reference |
|
ADORA2A |
rs2298383 |
C |
Reduced relative risk for developing anxiety with coffee consumption. |
|
|
ADORA2A |
rs5751876 |
T |
Increased relative risk for coffee-related anxiety. |
|
|
CYP1A2 |
rs762551 |
C |
High relative decrease in caffeine metabolic rate, high relative increase in cardiac risk. |
|
The table above contains the genes and their polymorphisms involved in coffee metabolism. The A to C polymorphism in the CYP1A2 gene reduces enzyme inducibility and activity, resulting in slowed metabolism of caffeine (Kotsopoulos, J. et al., 2009). The C>A substitution at position rs762551 shows that the CYP1A2 polymorphism has a significant enhancing effect on the inducibility of CYP1A2 by heavy coffee consumption (Djordjevic N. et al., 2010). The single nucleotide polymorphism (SNP) rs762551A>C has been reported to alter the enzyme activity. In Caucasians, the C allele has been found to be associated with an increased risk of hypertension due to a decrease in enzyme activity (Rodenburg, E. M. et al., 2012). It also showed a significant association between the rs762551 C variant and cancer risk in the CC versus AA genetic model (Wang, H. et al., 2012).
The TT genotype of the ADORA2A rs2298383 SNP has been shown to be associated with a reduced risk of depression compared to CC/CT genotypes. Additionally, this genotype has been associated with protection against sleep disturbance and attention deficit, two symptoms frequently seen in patients with depression (Oliveira, S. et al., 2019). ADORA2A has been shown to be responsible for the wakefulness-promoting effect of caffeine and the 1976T>C genotype (SNP rs5751876) to contribute to individual sensitivity to caffeine effects on sleep (Erblang, M. et al., 2019). Individuals with the T/T genotype of ADORA2A SNP rs5751876 (1976C/T) reported greater anxiety after 150 mg caffeine compared to other genotypic groups. The same polymorphism has been associated with panic disorder (PD) and it has been suggested that this variant poses a risk for anxiety states in general (Childs, E. et al., 2008). Adenosine receptor 2A (A2AR), one of four adenosine receptor subtypes, is found on almost all immune cells, including lymphocytes, monocytes, macrophages, and dendritic cells, and its activation increases the production of anti-inflammatory cytokines. Single nucleotide polymorphism (SNP) rs2298383 of the ADORA2A gene, which encodes A2AR, is a functional variant that can affect the rate of gene transcription due to its location in the regulatory sequence of the gene. In particular, recent literature data show that a decrease in the amount of A2AR protein increases the rate of inflammation (Cannata, A. et al., 2020).
REFERENCE
Alsene K, Deckert J, Sand P, de Wit H. Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 2003 Sep;28(9):1694-702. doi: 10.1038/sj.npp.1300232 . Epub 2003 Jun 25. PMID: 12825092.
Barcelos, R. P., Lima, F. D., Carvalho, N. R., Bresciani, G., & Royes, L. F. (2020). Caffeine effects on systemic metabolism, oxidative-inflammatory pathways, and exercise performance. Beslenme AraştıRması, 80, 1-17. https://doi.org/10.1016/j.nutres.2020.05.005
Cannata, A., Luca, C. D., Korkina, L. G., Ferlazzo, N., Ientile, R., Currò, M., Andolina, G., & Caccamo, D. (2020). The SNP rs2298383 Reduces ADORA2A Gene Transcription and Positively Associates with Cytokine Production by Peripheral Blood Mononuclear Cells in Patients with Multiple Chemical Sensitivity. International Journal of Molecular Sciences, 21(5). https://doi.org/10.3390/ijms21051858
Childs, E., Hohoff, C., Deckert, J., Xu, K., & Badner, J. (2008). Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 33(12), 2791. https://doi.org/10.1038/npp.2008.17
Djordjevic N, Ghotbi R, Jankovic S, Aklillu E. Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 -163C>A polymorphism. Eur J Clin Pharmacol. 2010 Jul;66(7):697-703. doi: 10.1007/s00228-010-0823-4. PMID: 20390257.
Erblang, M., Drogou, C., Gomez-Merino, D., Metlaine, A., Boland, A., Deleuze, J. F., Thomas, C., Sauvet, F., & Chennaoui, M. (2019). The Impact of Genetic Variations in ADORA2A in the Association between Caffeine Consumption and Sleep. Genes, 10(12). https://doi.org/10.3390/genes10121021
Kotsopoulos, J., Vitonis, A. F., Terry, K. L., Vivo, I. D., Cramer, D. W., Hankinson, S. E., & Tworoger, S. S. (2009). Coffee Intake, Variants in Genes Involved in Caffeine Metabolism and the Risk of Epithelial Ovarian Cancer. Cancer Causes & Control : CCC, 20(3), 335. https://doi.org/10.1007/s10552-008-9247-1
Oliveira, S., Ardais, A. P., Bastos, C. R., Gazal, M., Jansen, K., Souza, M., Kaster, M. P., Lara, D. R., & Ghisleni, G. (2019). Impact of genetic variations in ADORA2A gene on depression and symptoms: A cross-sectional population-based study. Purinergic Signalling, 15(1), 37-44. https://doi.org/10.1007/s11302-018-9635-2
Rodenburg, E. M., Eijgelsheim, M., Geleijnse, J. M., Amin, N., Van Duijn, C. M., Hofman, A., Uitterlinden, A. G., Stricker, B. H., & Visser, L. E. (2012). CYP1A2 and coffee intake and the modifying effect of sex, age, and smoking. The American Journal of Clinical Nutrition, 96(1), 182-187. https://doi.org/10.3945/ajcn.111.027102
Wang, H., Zhang, Z., Han, S., Lu, Y., Feng, F., & Yuan, J. (2012). CYP1A2 rs762551 polymorphism contributes to cancer susceptibility: A meta-analysis from 19 case-control studies. BMC Cancer, 12, 528. https://doi.org/10.1186/1471-2407-12-528