THE PROCESS IN MOTION

Why does the same cup not have the same effect on everyone?

Start the scene or choose a stage. The animation simplifies the mechanism; what follows gives the details and the available references.

▶ Play the process01One cup, two drinkers02One letter of difference03The slow one keeps it longer04The hearts of the slow ones05NAT2 and the receptor itself

One cup, two drinkers

Two people drink the same cup, at the same moment. The body eliminates the caffeine, and the speed of this elimination depends on a gene, CYP1A2, which exists in several versions.

Read the stages without animation

1. One cup, two drinkersTwo people drink the same cup, at the same moment. The body eliminates the caffeine, and the speed of this elimination depends on a gene, CYP1A2, which exists in several versions.
2. One letter of differenceThe CYP1A2 variant rs762551, the *1F allele, changes one letter of the DNA at position −163. AA homozygotes, who carry the letter A twice, are fast metabolizers; carriers of the C allele eliminate the molecule more slowly.
3. The slow one keeps it longerAt equal dose, a slow metabolizer keeps the caffeine active longer. Some studies suggest a better effect during exercise in fast metabolizers, but the result is not consistently found: the mechanism is established, its translation into performance is not.
4. The hearts of the slow onesCornelis and his coauthors studied in Costa Rica 2,014 cases of heart attack and 2,014 controls (JAMA, 2006): coffee was associated with an increased risk of nonfatal heart attack only in slow metabolizers, from two to three cups a day, and not in fast ones.
5. NAT2 and the receptor itselfNAT2, another transformation pathway, separates fast and slow acetylators according to geographic origin. ADORA2A codes for the A2A receptor; one of its variants is associated with increased anxiety, and its carriers spontaneously drink less coffee.

To remember: Some of the people coffee does not suit are reading out their genotype without knowing it.

Read the full article and its sources ↓

The CYP1A2 gene exists in several versions. The variant rs762551 (*1F allele, position −163C>A) distinguishes AA homozygotes, fast metabolizers, from carriers of the C allele, slower to eliminate the molecule. At equal dose, in the same cup, at the same moment, a slow metabolizer keeps caffeine active longer. Cornelis and coauthors showed in 2006 in JAMA, on 2,014 cases of heart attack and 2,014 controls in Costa Rica, that coffee consumption was associated with an increased risk of nonfatal heart attack only in slow metabolizers, from two to three cups a day, and not in fast ones.

Some studies suggest that fast metabolizers get a better stimulant effect from caffeine during exercise, but this result is not consistently found, in basketball and cycling in particular, and the 2020 collection explicitly flags this disagreement: the mechanism is established, its translation into performance is not.

Cornelis et al., Coffee, CYP1A2 genotype, and risk of myocardial infarction, JAMA 295 (2006); MDPI 2020, p. 11; LC ch. 19

Two other genes matter. NAT2, another transformation pathway, separates acetylator populations, fast and slow, according to geographic origin. ADORA2A codes for the A2A receptor itself; one of its variants is associated with increased anxiety after consumption, and its carriers spontaneously drink less coffee without anyone having tested them. Some of the people who explain that coffee does not suit them are reading out their genotype without knowing it.

This also contaminates observational studies: if heavy and light drinkers differ by a gene, they differ by everything that gene entails elsewhere. One study in the collection tests the measurement of urinary metabolites as a routine test to find out one's profile; the proposed formulas sometimes classify the same subject differently. A lead, not yet a tool.

MDPI 2020, pp. 93, 239-253; LC ch. 19