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

Abstract

This study investigated whether four single nucleotide polymorphisms (SNPs) moderated caffeine effects on vigilance and performance in a double-blind and crossover total sleep deprivation (TSD) protocol in 37 subjects. In caffeine (2 × 2.5 mg/kg/24 h) or placebo-controlled condition, subjects performed a psychomotor vigilance test (PVT) and reported sleepiness every six hours (Karolinska sleepiness scale (KSS)) during TSD. EEG was also analyzed during the 09:15 PVT. Carriers of the TNF-α SNP A allele appear to be more sensitive than homozygote G/G genotype to an attenuating effect of caffeine on PVT lapses during sleep deprivation only because they seem more degraded, but they do not perform better as a result. The A allele carriers of COMT were also more degraded and sensitive to caffeine than G/G genotype after 20 h of sleep deprivation, but not after 26 and 32 h. Regarding PVT reaction time, ADORA2A influences the TSD effect but not caffeine, and PER3 modulates only the caffeine effect. Higher EEG theta activity related to sleep deprivation was observed in mutated TNF-α, PER3, and COMT carriers, in the placebo condition particularly. In conclusion, there are genetic influences on neurobehavioral impairments related to TSD that appear to be attenuated by caffeine administration. (NCT03859882).

Genetic Markers of Differential Vulnerability to Sleep Loss in Adults

“…The T1083C polymorphism (SNP-ID: rs5751876) in the adenosine A2A receptor ( ADORA2A ) gene also contributes to an individual’s neurobehavioral vulnerability to sleep loss: a recent study found that T allele carriers had worse vigilant attention performance (greater number of PVT lapses) than C/C individuals after 32 h TSD [ 67 ]. Similarly, another study showed that C/T carriers exhibited greater PVT performance resilience during chronic SR compared with T/T carriers [ 68 ].…”

“…One study found that caffeinated coffee mitigated performance deficits on tasks of vigilant attention and executive control, but not self-rated sleepiness, induced by five consecutive nights of SR in C/C allele carriers [ 71 ]. Furthermore, caffeine counteracted 40 h TSD-induced decrements in PVT performance in non-HT4 allele carriers but was not effective in individuals with the HT4 haplotype [ 69 ], although another study showed that the ADORA2A genotype did not influence the mitigatory effect of caffeine on PVT performance during 38 h TSD [ 67 ]. In addition, although A 1 adenosine receptor (A 1 AR) availability has been linked to the mitigatory effects of recovery sleep on neurobehavioral performance following 52 h TSD, this effect was not moderated by the ADORA2A genotype [ 72 ].…”

“…The PER3 C7827519G SNP (SNP-ID: rs228697) has also been studied in relation to interindividual differences in responses to sleep loss. However, a study involving 38 h TSD found neither an association between PER3 genotype and neurobehavioral response to TSD, nor an interaction between PER3 genotype, TSD, and caffeine on PVT performance at any point throughout the protocol [ 67 ].…”

“…A recent study also investigated the potential effect of this COMT polymorphism on performance impairment during TSD both independent from, and related to, the mitigatory effect of caffeine. While no main effect of COMT genotype was observed on PVT performance or KSS scores overall, the study found that, after 20 h TSD, but not after 26 h or 32 h TSD, Met allele carriers had more PVT lapses than Val/Val individuals in the placebo condition [ 67 ]. Notably, this genotypic performance difference was not observed when participants were provided caffeine, suggesting its beneficial impact [ 67 ].…”

“…While no main effect of COMT genotype was observed on PVT performance or KSS scores overall, the study found that, after 20 h TSD, but not after 26 h or 32 h TSD, Met allele carriers had more PVT lapses than Val/Val individuals in the placebo condition [ 67 ]. Notably, this genotypic performance difference was not observed when participants were provided caffeine, suggesting its beneficial impact [ 67 ]. Please see the Section 4 entitled, “Countermeasures for the Detrimental Neurobehavioral Effects of Sleep Deprivation” for more details about the potential link between genetic polymorphisms and mitigation strategies (also see Figure 1 ).…”