Effects of Acute Caffeine Intake on Insulin-Like Growth Factor-1 Responses to Total Sleep Deprivation: Interactions with <i>COMT</i> Polymorphism – A Randomized, Crossover Study

Abstract

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