Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors in overweight subjects (GOLDN population).

Despite the importance of total energy intake in circadian system regulation, no study has related human CLOCK gene polymorphisms and food-intake measures. The aim of this study was to analyze the associations of CLOCK single-nucleotide polymorphisms (SNPs) with food intake and to explore the specific role of the cytokine system. A total of 1100 individual participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study were included. Dietary intake was estimated with a validated questionnaire. Interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP1), tumor necrosis factor-alpha (TNF-alpha), IL-2 soluble receptor-alpha (IL-2sR-alpha) and adiponectin plasma concentrations were measured. Our results showed that four of five CLOCK SNPs selected were significantly associated with total energy intake (P<0.05). For SNP rs3749474, the energy intake and total fat, protein and carbohydrate intakes were significantly higher in minor allele carriers than in non-carriers. Frequency of the minor allele was greater in subjects with high energy intake than in those with low intake. Subjects with the minor allele were 1.33 times more likely to have high energy intake than non-carriers (95% CI 1.09-1.72, P=0.0350). All CLOCK SNPs were associated with plasma cytokine values, in particular with those that were highly correlated with energy intake: MCP1, IL-6 and adiponectin. Interestingly, minor allele carriers with high energy intake showed decreased cytokine values, which could be related with a lower anorectic effect and decreased sleep in these subjects. In conclusion, we show a novel association of genetic variation at CLOCK with total energy intake, which was particularly relevant for SNP rs3749474. Associations could be mediated through the alteration of cytokine levels that may influence energy intake and sleep pattern.