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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.

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