Effects of acute caffeine intake on Insulin-like Growth Factor-1 responses to total sleep deprivation: interactions with COMT polymorphism, a randomized, cross over study

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 hours) or placebo-controlled condition, blood sampling was performed at 1h (08:00, baseline), 11h, 13h, 25h (08:00 next day), 35h, and 37h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 hours of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values (+/- SEM): 118 +/- 8, 121 +/- 10 and 121 +/- 10 versus 105 +/- 7 ng/ml for A/A, 127 +/- 11, 128 +/- 12 and 129 +/- 13 versus 120 +/- 11 ng/ml for G/G, and 106 +/- 9, 110 +/- 10 and 106 +/- 10 versus 101 +/- 8 ng/ml for G/A, after 25, 35 and 37 h of wakefulness versus 1h; p<0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 +/- 26, 107 +/- 27 and 106 +/- 26 versus 100 +/- 25 ng/ml for A/A genotype, at 25, 35 and 37 h of wakefulness versus 1h; p<0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 +/- 5 versus 113 +/- 6 ng/ml) (p<0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Discussion/Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake. (NCT03859882).