rs5751876
badMag 3.5This is a synonymous variant in the ADORA2A gene — it does not change the protein's amino acid sequence.
Key Literature Trait Associations
Caffeine Sensitivity / Sleep Disruption
The adenosine A2A receptor (ADORA2A) is the primary target through which caffeine promotes wakefulness. Adenosine builds up during waking hours and promotes sleepiness; caffeine blocks the A2A receptor. TT homozygotes are more sensitive to caffeine: they experience greater alertness, anxiety, and sleep disruption from the same dose. C allele carriers are relatively caffeine-tolerant. This explains why some people can drink espresso after dinner and sleep fine, while others are wired for hours.
Panic disorder
rs5751876 has been replicated as a susceptibility variant for panic disorder, particularly panic disorder with agoraphobia, across multiple European cohorts. The T allele and its LD partners (rs5751862, rs2298383, rs3761422) associate with both clinical panic disorder and elevated anxiety-related personality scores. Functional analyses suggest rs2298383 may be the causal variant in this haplotype block. The mechanistic link is plausible: caffeine challenge in TT homozygotes recapitulates panic-like anxiety, and A2A receptor signaling modulates fear and arousal circuits in the amygdala and hippocampus.
Platelet reactivity on ticagrelor
Among 244 ACS or PCI patients on ticagrelor, C-allele carriers of rs5751876 had significantly higher rates of high residual platelet reactivity (HRPR) compared to T/T homozygotes (adjusted OR=4.63, 95% CI 1.02–21.01, p=0.048). Ticagrelor's antiplatelet mechanism involves adenosine re-uptake inhibition alongside P2Y12 blockade; C-allele carriers may have reduced A2A-mediated platelet inhibitory signaling. The finding is clinically relevant for predicting treatment efficacy in coronary intervention settings, though the small sample and wide confidence interval require cautious interpretation.
Antipsychotic-induced akathisia
In a pharmacogenomic study of 127 non-acute schizophrenia patients on long-term antipsychotic therapy, rs5751876 was significantly associated with akathisia (p=0.015). This represents the first reported link between ADORA2A polymorphisms and antipsychotic adverse effects, consistent with adenosine's modulatory role in dopaminergic pathways relevant to movement side effects. The small sample size and single-centre design limit generalizability; replication in larger cohorts is needed.
Gilles de la Tourette syndrome
In a Polish case-control study, the T allele of rs5751876 was significantly overrepresented among 162 Tourette syndrome patients compared to 270 healthy controls (p=0.017). The T allele was also less frequent in GTS patients with comorbid ADHD (p=0.022), suggesting it may modulate phenotypic expression rather than simply conferring overall disease risk. This finding awaits independent replication in other populations and should be interpreted cautiously given the single-population design and modest sample size.
Methotrexate response in rheumatoid arthritis
In a study of 281 North Indian rheumatoid arthritis patients, the T allele of rs5751876 was associated with poor methotrexate response (OR=1.55, 95% CI 1.01–2.37, p=0.04). Methotrexate's anti-inflammatory mechanism partly involves increased extracellular adenosine, which signals through ADORA2A to suppress immune activation; T-allele-mediated differences in receptor function may blunt this pathway. A separate Slovenian cohort found carriers of the rs5751876 polymorphic allele less likely to experience methotrexate adverse events (p=0.018), suggesting the variant has pleiotropic effects on both efficacy and tolerability. Findings remain preliminary and population-specific.
▶Research that mentions this SNP (3)
▶Screening individuals with intellectual disability, autism and Tourette's syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster.ReviewMarta Sánchez Delgado et al.(2014)· American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
This review examines the genetic and epigenetic basis of Tourette Syndrome (TS), a neurodevelopmental disorder with high heritability (0.45-0.77). The paper reviews candidate gene associations including variants in SLITRK1 (rs9593835, rs9546538, rs9531520), DRD2/ANKK1 (rs1800497), ADORA1/ADORA2A (rs2228079, rs5751876), and other dopaminergic genes, along with a large GWAS in 1285 cases and 4964 controls highlighting rs7868992 in COL27A1. The review proposes that epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) may link genetic susceptibility with environmental factors in TS pathogenesis.
▶Three polymorphisms of the eNOS gene and plasma levels of metabolites of nitric oxide in depressed Japanese patients: a preliminary reportAssociationN=375Atsuko Ikenouchi‐Sugita et al.(2011)· Human Psychopharmacology: Clinical and Experimental
This case-control study identified biallelic combinations of genetic variants associated with vasovagal syncope using Bayesian statistical analysis in 175 VVS patients and 200 controls. Eleven pairwise combinations of SNPs from neurohumoral regulation genes and the 2q32.1 locus were identified, with five showing significant epistatic interactions. Key associations included COMT*G with OR=2.04 (p=0.0015) and COMT*G + ADORA2A*C/C with OR=2.78 (p<0.001), suggesting a common genetic background between syncope and cardiovascular pathology.
▶Coffee, caffeine‐related genes, and Parkinson's disease: A case–control studyAssociationN=1,208Maurizio F. Facheris et al.(2008)· Movement Disorders
A case-control study of 604 Parkinson's disease case-control pairs examining the association between coffee drinking and genetic variants in caffeine-related genes. The study found no significant association between coffee consumption (ever/never or dose-dependent) and PD risk in the overall sample or stratified analyses, and no evidence for gene-environment interactions between coffee and variants in ADORA2A (rs5751876, rs3032740) or CYP1A2 (rs35694136, rs762551), except for a borderline association with ADORA2A rs3032740 in men (OR=0.71, 95% CI: 0.52-0.96, p=0.03).
Gene information from NCBI Gene. Variant classifications from ClinVar.
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