|Lai, Chao Qiang|
Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2009
Publication Date: 11/4/2009
Citation: Garaulet, M., Lee, Y., Shen, J., Parnell, L.D., Arnett, D.K., Tsai, M.Y., Lai, C., Ordovas, J.M. 2009. Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors. Human Molecular Genetics. 18(3):364-369. Interpretive Summary: Despite the importance of total energy intake in the regulation of natural circadian (daily) rhythms, no study has examined the influence of food intake measures and variations in the human CLOCK gene, a central component of the circadian system. Thus, the aim of this study was to investigate associations of five CLOCK gene variants with food-intake and to explore the particular role of cytokines, specialized cell signalling and activating molecules, in this connection. The five gene variants were assayed in 1100 White American persons for whom dietary intakes were calculated from a validated food frequency questionnaire and for whom five specific cytokine measures were available. Our results indicate that four of the CLOCK gene variants were significantly associated with total energy-intake. For one variant, rs3749474, energy-intake and total fat, protein and carbohydrate intakes were significantly higher in persons carrying the less common version of the variant than in non-carriers. Consistently, the frequency of this less common variant was about 1.33-fold greater in persons with high energy-intake than in those with low intake. In addition, all five CLOCK gene variants analyzed showed significant associations with blood levels of three cytokines that are known to be highly correlated with energy intake: MCP1, IL6 and adiponectin. Interestingly, persons carrying one or two copies of the less common version of variant rs3749474 presented lower levels of the cytokines and this could be related to both decreased appetite and sleep in these persons. In conclusion, we demonstrate the novel association of genetic variation at the CLOCK gene with total energy-intake. Furthermore, this association could be mediated through the alteration of cytokine levels which in turn may influence energy intake and sleep pattern.
Technical Abstract: 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 investigate associations of five CLOCK single-nucleotide-polymorphisms (SNPs) with food-intake and to explore the particular role of the cytokine system in this connection. 1100 individuals, participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, were included. Dietary intake was estimated with a validated questionnaire. IL6, MCP1, TNF, IL2sRalpha and adiponectin plasma concentrations were also measured. Our results showed that four of five CLOCK SNPs selected were significantly associated with total energy-intake (P<0.05). For SNP rs3749474, energy-intake and total fat, protein and carbohydrate intakes (g/day) were significantly higher in minor allele carriers than in non-carriers. Consistently, the frequency of the minor allele was greater in subjects with high energy-intake than in those with low intake. After multivariate adjustment, subjects with 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 highly correlated with energy intake: MCP1 (P<0.0001), IL6 (P<0.01) and adiponectin (P<0.0001). Interestingly, minor allele carriers with high energy-intake presented decreased cytokine values, which could be related a lower anorectic effects and decreased sleep in these subjects. Further haplotype analyses supported a significant effect of CLOCK variants on energy-intake (P=0.002) and on plasma-cytokines (P=0.0001). In conclusion, we demonstrate the novel association of genetic variation at CLOCK with total energy intake. Furthermore, the association could be mediated through the alteration of cytokine levels that may influence energy intake and sleep pattern.