The Impact of Genetic Variations in ADORA2A in the Association between Caffeine Consumption and Sleep

Abstract

ADORA2A has been shown to be responsible for the wakefulness-promoting effect of caffeine and the 1976T>C genotype (SNP rs5751876, formerly 1083T>C) to contribute to individual sensitivity to caffeine effects on sleep. We investigate the association between six single nucleotide polymorphisms (SNP) from ADORA2A and self-reported sleep characteristics and caffeine consumption in 1023 active workers of European ancestry aged 18–60 years. Three groups of caffeine consumers were delineated: low (0–50 mg/day, less than one expresso per day), moderate (51–300 mg/day), and high (>300 mg/day). We found that at caffeine levels higher than 300 mg/day, total sleep time (TST) decreased (F = 13.9, p < 0.01), with an increase of insomnia (ORa [95%CI] = 1.5 [1.1–1.9]) and sleep complaints (ORa [95%CI] = 1.9 [1.1–3.3]), whatever the ADORA2A polymorphism. Odds ratios were adjusted (ORa) for sex, age, and tobacco. However, in low caffeine consumers, lower TST was observed in the T allele compared to homozygote rs5751876 and rs3761422 C carriers. Conversely, higher TST was observed in rs2298383 T allele compared to C and in rs4822492G allele compared to the homozygote C (p < 0.05). These 4 SNPs are in strong linkage disequilibrium. Haplotype analysis confirmed the influence of multiple ADORA2a SNPs on TST. In addition, the rs2298383 T and rs4822492 G alleles were associated with higher risk of sleep complaints (Ora = 1.9 [1.2–3.1] and Ora = 1.5 [1.1–2.1]) and insomnia (Ora = 1.5 [1.3–2.5] and Ora = 1.9 [1.3–3.2). The rs5751876 T allele was associated with a decreased risk of sleep complaints (Ora = 0.7 [0.3–0.9]) and insomnia (Ora = 0.5 [0.3–0.9]). Our results identified ADORA2A polymorphism influences in the less-than-300-mg-per-day caffeine consumers. This opens perspectives on the diagnosis and pharmacology of sleep complaints and caffeine chronic consumption.

Genetic Determinants of Neurobehavioral Responses to Caffeine Administration during Sleep Deprivation: A Randomized, Cross Over Study (NCT03859882)

“…Caffeine seems to attenuate the genetic influence on vigilance impairments. We selected four SNPs that have been previously identified as potential genetic mechanisms of vulnerability to sleep loss and/or caffeine intake: the proinflammatory cytokine TNF-α involved in the regulation of immune cells, ADORA2A the adenosine A2A receptor-related gene, PER3 the circadian gene, and COMT the gene for catechol-O-methyltransferase (COMT), an enzyme critical for the breakdown of catecholamines [ 12 , 13 , 14 , 16 , 19 , 23 ].…”

“…Regarding genetic interindividual vulnerability to sleep loss and/or caffeine efficiency, acute caffeine administration or habitual consumption have been studied. The most studied rs5751876 ADORA2A (gene of A2A receptor, formally designated as 1976C/T or 1083C/T) was found associated with habitual caffeine consumption [ 19 ]. This polymorphism contributed also to individual sensitivity to the effects of habitual caffeine consumption on sleep [ 19 , 20 ] and is associated with the anxiogenic response to caffeine [ 21 , 22 ].…”

“…The most studied rs5751876 ADORA2A (gene of A2A receptor, formally designated as 1976C/T or 1083C/T) was found associated with habitual caffeine consumption [ 19 ]. This polymorphism contributed also to individual sensitivity to the effects of habitual caffeine consumption on sleep [ 19 , 20 ] and is associated with the anxiogenic response to caffeine [ 21 , 22 ]. The Bodenman et al study [ 23 ] is the only one demonstrating that the haplotype HT4 carriers of ADORA2A performed faster on the PVT than carriers of non-HT4 haplotype alleles during TSD, and caffeine failed to counteract the PVT impairment and the rebound of slow-wave activity (SWA) in recovery sleep.…”

ADORA2A C Allele Carriers Exhibit Ergogenic Responses to Caffeine Supplementation

“…Additionally, given the small number of ADORA2A TT homozygotes in our sample, we could not assess whether TT homozygotes experience different responses to caffeine ingestion compared with C allele carriers, an area that should be explored in future research. The low number of participants classified as TT homozygotes could be explained by the estimate that around 85% of the population possess the CC/CT genotype at rs5751876 [39].…”

Energy Drinks and Sports Performance, Cardiovascular Risk, and Genetic Associations; Future Prospects

“…What is more, polymorphism c.1976T>C (rs5751876) in gene ADORA2A (adenosine A2A receptor) has been shown to modulate sleep-wake activity [99], contribute to individual sensitivity to caffeine's effects on sleep [100], increasing susceptibility to caffeineinduced anxiety [101,102].…”