rs5751876 — ADORA2A 1976T>C

The Caffeine Sensitivity Gene — Why Coffee Keeps Some People Awake

Every cup of coffee triggers a molecular contest inside your brain. Caffeine works by blocking adenosine¹¹ adenosine
A neurotransmitter that accumulates during wakefulness and promotes sleepiness. Adenosine is essentially your brain's "tiredness signal" — it builds up the longer you're awake and dissipates during sleep from binding to its receptors, particularly the A2A receptor²² A2A receptor
One of four adenosine receptor subtypes (A1, A2A, A2B, A3). The A2A receptor is concentrated in the striatum and plays a central role in sleep-wake regulation and anxiety encoded by the ADORA2A gene. The rs5751876 variant determines how strongly your brain responds to this caffeine blockade — making some people jittery after a single espresso while others can drink coffee at dinner and sleep soundly.

What makes this variant unusual is its split personality: the T allele increases vulnerability to caffeine-induced anxiety, while the C allele increases vulnerability to caffeine-induced sleep disruption. These are distinct neurological pathways, and your genotype shifts the balance between them.

The Mechanism

Despite being a synonymous variant³³ synonymous variant
A DNA change that doesn't alter the protein's amino acid sequence. The codon still codes for tyrosine at position 361. However, synonymous variants can affect gene expression through changes in mRNA stability, splicing, or regulatory element function (Tyr361Tyr), rs5751876 has robust, replicated associations with multiple phenotypes. The variant itself likely isn't the direct cause — instead, it sits in tight linkage disequilibrium⁴⁴ linkage disequilibrium
When two genetic variants are inherited together more often than expected by chance, because they're physically close on the chromosome. This means rs5751876 reliably tags the true functional variant nearby with several nearby variants (rs2298383, rs3761422, rs4822492) that may affect ADORA2A promoter activity and receptor expression levels in the brain.

Brain imaging studies⁵⁵ Brain imaging studies
Hohoff et al. 2020. ADORA2A variation and adenosine A1 receptor availability in the human brain. Translational Psychiatry have shown that rs5751876 genotype influences adenosine A1 receptor availability across 30 of 31 brain regions examined, with particularly strong effects in anxiety-related regions including the amygdala and hippocampus. This suggests the variant modulates the entire adenosine signaling system, not just the A2A receptor itself.

The Evidence

The caffeine-anxiety link was first established by Alsene et al.⁶⁶ Alsene et al.
Alsene K et al. Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology, 2003, who gave 94 healthy infrequent caffeine users 150mg of caffeine and found that T/T carriers reported significantly greater anxiety increases than C/C carriers. Childs et al.⁷⁷ Childs et al.
Childs E et al. Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology, 2008 replicated this in 102 participants across four caffeine doses (0, 50, 150, 450mg), confirming the T/T genotype showed the greatest anxiety response at the 150mg dose (F(2,98)=3.5, p<0.05).

The sleep side of the story came from Retey et al.⁸⁸ Retey et al.
Retey JV et al. A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther, 2007, who surveyed over 4,300 people about their caffeine sensitivity and then performed EEG sleep studies. C-allele carriers showed caffeine-induced changes in brain electrical activity during sleep that closely resembled the patterns seen in insomnia patients. This finding was replicated in a GWAS of 2,402 Australian twins⁹⁹ GWAS of 2,402 Australian twins
Byrne EM et al. A genome-wide association study of caffeine-related sleep disturbance. Sleep, 2012 (OR 0.62 for proxy SNPs in complete LD, p=0.019) — one of the few candidate-gene associations from the pre-GWAS era to survive genome-wide replication.

The anxiety association traces back even further: Deckert et al.¹⁰¹⁰ Deckert et al.
Deckert J et al. Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder. Mol Psychiatry, 1998 first linked the T allele to panic disorder in 1998, and a 2010 replication study¹¹¹¹ 2010 replication study
Deckert J et al. Evidence for association of risk variants with panic disorder and anxious personality. J Psychiatr Res, 2010 with 531 panic disorder patients and 540 controls confirmed the association and extended it to anxious personality traits.

Practical Implications

The most actionable finding is the caffeine-genotype interaction. A large French cohort study¹²¹² large French cohort study
Erblang M et al. The Impact of Genetic Variations in ADORA2A in the Association between Caffeine Consumption and Sleep. Genes, 2019 (N=1,023) found that among low caffeine consumers (<300mg/day), T/T carriers had a decreased risk of insomnia (OR 0.5) compared to C/C carriers. But at high consumption levels (>300mg/day), genotype differences vanished — all groups showed sleep disruption, suggesting that heavy caffeine use overwhelms any genetic protection.

An important nuance: tolerance develops. Rogers et al.¹³¹³ Rogers et al.
Rogers PJ et al. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology, 2010 showed that frequent caffeine consumption substantially blunts the anxiogenic effect even in genetically susceptible individuals, though it comes at the cost of withdrawal symptoms¹⁴¹⁴ withdrawal symptoms
Regular caffeine users who skip their usual dose experience fatigue, headache, and difficulty concentrating — the mirror image of caffeine's acute benefits when caffeine is withheld.

Interactions

The most important interaction is with CYP1A2 (rs762551), which controls caffeine metabolism speed. ADORA2A determines how sensitive your receptors are to caffeine, while CYP1A2 determines how fast your liver clears it. A person who is both a slow CYP1A2 metabolizer (rs762551 C-carriers) and an ADORA2A T-carrier (anxiety-sensitive) faces a double challenge: caffeine lingers in the bloodstream longer and simultaneously hits the adenosine receptors harder. For these individuals, even a single afternoon coffee can trigger anxiety and disrupt that night's sleep.

Conversely, fast CYP1A2 metabolizers with ADORA2A C/C genotype have the highest caffeine tolerance — they clear it quickly and their receptors are less reactive. These are the people who genuinely can drink coffee at dinner with no consequences.