rs762551 — CYP1A2 *1F

CYP1A2 - The Caffeine Gene

CYP1A2 is the enzyme responsible for metabolizing approximately 95% of caffeine in the body. Your CYP1A2 genotype largely determines whether you are a "fast" or "slow" caffeine metabolizer, which has implications not just for how coffee affects you but potentially for your cardiovascular health.

The Mechanism

The CYP1A2*1F variant¹¹ rs762551 is located in intron 1 of the gene and affects the inducibility²² Inducibility: how readily the gene is switched on in response to external triggers of CYP1A2 expression. The A allele is associated with higher enzyme inducibility - meaning the enzyme is more readily upregulated in response to inducers like caffeine itself, cigarette smoke, and cruciferous vegetables. The C allele has lower inducibility, resulting in slower caffeine clearance. The functional significance was first described by Sachse et al. in 1999³³ Sachse et al. in 1999
Sachse C et al. Functional significance of a C>A polymorphism in intron 1 of CYP1A2. Br J Clin Pharmacol, 1999.

Coffee and Heart Health

A landmark study by Cornelis et al. (2006) in JAMA⁴⁴ Cornelis et al. (2006) in JAMA
Cornelis MC et al. Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction. JAMA, 2006 found that slow caffeine metabolizers (CC genotype) who drank 2-3 cups of coffee daily had a significantly increased risk of heart attack, while fast metabolizers (AA genotype) actually showed a protective effect from the same amount of coffee. This gene-diet interaction suggests that the cardiovascular effects of coffee depend on how quickly you clear caffeine from your system. A follow-up study by Palatini et al.⁵⁵ Palatini et al.
Palatini P et al. CYP1A2 genotype modifies the association between coffee intake and hypertension risk. J Hypertens, 2009 confirmed the interaction with hypertension risk.

The Half-Life Difference

Fast metabolizers (AA) clear caffeine with a half-life of about 4 hours, while slow metabolizers (CC) may have a half-life of 8-12 hours or more. This means a cup of coffee at noon could still have significant caffeine levels in your blood at midnight if you are a slow metabolizer, potentially disrupting sleep architecture even if you feel you sleep "fine."

Beyond Caffeine

CYP1A2 also metabolizes several medications including theophylline (asthma), clozapine (schizophrenia), and melatonin. Slow metabolizers may need dose adjustments for these drugs. The enzyme is also involved in the bioactivation of certain procarcinogens⁶⁶ Procarcinogens are harmless until the body's enzymes convert them into cancer-causing compounds from grilled meat, making its activity relevant to cancer risk assessment.

Practical Implications

If you are AA (fast metabolizer), moderate coffee consumption (2-4 cups daily) appears safe and potentially beneficial. If you are CC (slow metabolizer), limiting caffeine to 1-2 cups consumed in the morning is prudent. Pay attention to sleep quality - slow metabolizers often do not realize that afternoon caffeine is compromising their sleep.