Why do we respond differently to caffeine?

Why do we respond differently to caffeine?

by Dr. Haran Sivapalan – Science Writer at FitnessGenes   Give two people an identical cup of coffee, brewed under identicalcircumstances, and the ...

by Dr. Haran Sivapalan – Science Writer at FitnessGenes


Give two people an identical cup of coffee, brewed under identical
circumstances, and the chances are that each person will respond differently.
Why is this?

Nature vs nurture

It could be that one of the people, let’s call him Jacques, is a smoker. We
know that smoking almost doubles the clearance of caffeine, so that caffeine
lingers for less time in Jacque’s bloodstream. Consequently, for Jacques, the
buzz of a cup of coffee is much shorter-lived.

In contrast to Jacques, Jillian never touches tobacco. Instead, she prefers to
sip on grapefruit juice, which has been shown to reduce caffeine clearance,
dramatically prolonging its half-life in the body by 31%. Accordingly, Jillian
feels the effects of caffeine – which include increased alertness, higher heart
rate and rises in blood pressure – for a longer time.

Such differences between Jacques’ and Jillian’s diet and lifestyle are classified
by biologists as “environmental”. If variation in how we respond to caffeine can
be framed within the age-old “nature vs nurture” debate, then environmental
differences fall firmly in the “nurture” camp. That leaves “nature” – or, in other
words, differences in our genes.

Genes as a source of variation

Genes are stretches of DNA that code for proteins; and proteins are arguably
the most important class of molecules in our body. They include structural
proteins, such as collagen, that give us our shape and form; receptors in our
brain (e.g. dopamine receptors) that govern complex behaviours; and
enzymes, including those that break down the caffeine in a latte macchiato.

The beauty of our DNA code is that its exact sequence (i.e. the precise order
of A’s, C’s, G’s, and T’s) determines the type, structure and activity of the
proteins that we produce. Furthermore, it follows that any changes in our DNA
sequence can potentially alter the properties of these produced proteins.
Given that proteins influence everything from our eye colour to
our likelihood of getting a divorce, small changes in our DNA code can have profound downstream effects on the way our body works.

Far from being the sole preserve of radioactive spider bites and mutant
experiments gone wrong, changes in stretches of our DNA sequence are
actually fairly common. Scattered throughout the human genome are small
single-letter changes called Single Nucleotide Polymorphisms or SNPs
(pronounced “snips”). For example, instead of the letter ‘C’ at one site in our
DNA sequence, there may instead be the letter ‘T’.

SNPs, which, by definition, are present in more than 1% of the population, are
the most common source of genetic variation between us. By changing our
DNA sequence and subsequently altering the structure, activity or quantity of
proteins that we produce, SNPs can cause two individuals to respond
remarkably differently to diet, drugs, exercise and even life events.

Getting back to the black stuff, and SNPs may also partly explain why
Jacques and Jillian respond differently to caffeine.

Our CYP1A2 gene and caffeine metabolism

Every time we drink a cup of coffee, around 90% of the caffeine is broken
down or ‘metabolised’ by an enzyme found in the liver called CYP1A2.

Recall that proteins (such as enzymes) are encoded by stretches of DNA that
we call “genes.” In this respect, our CYP1A2 enzyme is coded for by our
CYP1A2 gene.

At one specific point in the DNA sequence of the CYP1A2 gene, however, a
SNP causes a change from the letter “C” to the letter “A”.

It turns out that this tiny single letter change has a large effect on our CYP1A2
enzyme. The letter “A” codes for a CYP1A2 enzyme that is much more highly
“inducible”, meaning that it is produced much more readily in response to
caffeine. Consequently, this form of the enzyme is much more active and
effective at breaking down caffeine, particularly when concentrations of
caffeine in the bloodstream are high. 

As a result of the CA SNP then, we have two possible CYP1A2 gene
variants or “alleles”: the bog standard, normal enzyme variant (or “wildtype
allele”) with the letter “C”, and the higher activity, SNP-containing variant (or
“mutant allele”) with the letter “A”.

Genes, however, like shoes, the animals of Noah’s ark, or buses in London
once you’ve waited ages for one, come in pairs. We inherit one copy from our
mother and another copy from our father.

Jacques has inherited two copies of the “A” allele, giving him a genetic
makeup or ‘genotype’ of AA. This AA genotype makes him a fast
Rapid Metabolizer of caffeine.

As a result of this genetic makeup, Jacques, and other fast metabolizers like
him, produce the higher activity and more highly inducible CYP1A2 enzyme.
Consequently, fast metabolizers clear caffeine much more effectively, are
better able to tolerate higher caffeine intakes (3 or more cups of coffee per
day) and may experience the effects of caffeine less strongly. For example, studies show that fast metabolizers have significantly smaller rises in blood
pressure one hour after drinking coffee. 

Conversely, Jillian experiences much more pronounced increases in blood
pressure every time she drinks a coffee. This is because, by virtue of her
genetic makeup, Jillian is a slow metabolizer of caffeine.

She has inherited two copies of the ‘C’ allele of the CYP1A2 gene, giving her
the CC genotype, which codes for the (relatively speaking) less inducible and
less active CYP1A2 enzyme. Similarly, anyone carrying one copy each of the
‘A’ and ‘C’ allele, thereby having the AC genotype, are also slow metabolisers,
who break down caffeine more slowly and feel the effects of caffeine for a
longer time.

Our ADORA2A gene and sensitivity to caffeine

Anybody who’s imbibed several cups of coffee in order to meet a looming
work deadline will attest to the fact that caffeine is, of course, a stimulant drug.
The same people may also agree that caffeine can precipitate symptoms of
anxiety. Many of these psychostimulant effects, including one of the prime
reasons we reach for a cup of coffee each morning - increased wakefulness,
result from the action of caffeine on our brain’s adenosine receptors.

Caffeine is what we term an “adenosine receptor antagonist”. This means it
binds to and blocks our adenosine receptors, preventing them from being

One of the key types of adenosine receptor blocked by caffeine is the
adenosine 2a receptor, which is encoded by our ADORA2A gene. Evidence
suggests that variants of this gene can affect how likely we are to experience
anxious symptoms after drinking coffee.

A SNP within the ADORA2A gene causes a change from the letter ‘C’ to the
letter ‘T’, creating two variants / alleles: the ‘C’ allele and the ‘T’ allele. Jillian,
and people like her, with two copies of the ‘T’ allele (i.e. with the TT genotype)
have been shown to experience greater feelings of anxiety after consuming
150 mg of caffeine. To put that figure in perspective, a 30 – 50ml shot of
espresso contains about 63mg of caffeine.

In another study that is reminiscent of A Clockwork Orange, subjects with different ADORA2A gene variants were shown deeply unpleasant, neutral and
pleasant images and then their eyelids monitored for blinking activity. The
researchers were assessing something known as our “startle reflex” – a rapid,
involuntary response to a sudden or surprising stimulus e.g. a loud noise.
Generally speaking, the magnitude of someone’s blink serves as a proxy of
how emotionally aroused they are: the more anxious you are, the bigger your
eye blink.

Compared to people with CC and CT genotypes, those with the TT genotype
(e.g. Jillian) showed a much greater blink response to unpleasant images after
consuming 300mg of caffeine. In other words, caffeine made them more

In an effort to obviate such caffeinated anxiety, Jillian makes far fewer trips to
her local café than Jacques, mirroring a trend for reduced caffeine
consumption shown in other people with the TT genotype. Zooming out, it
becomes apparent how a simple, invisible single-letter change in our DNA
sequence can considerably influence complex, social behavior such as


Dr Haran Sivapalan is the scientific copywriter for FitnessGenes, a home DNA analysis company specializing in genes that impact exercise, nutrition and lifestyle. Your rate of caffeine breakdown is just one of 70+ traits FitnessGenes report on, with a new trait delivered every Tuesday. Learn more at fitnessgenes.com.

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