|Lai, Chao Qiang|
Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/30/2009
Publication Date: 10/21/2009
Citation: Garaulet, M., Lee, Y., Shen, J., Parnell, L.D., Arnett, D.K., Tsai, M.Y., Lai, C., Ordovas, J.M. 2009. CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids. American Journal of Clinical Nutrition. 90(6):1466-1475. Interpretive Summary: As disruption of the circadian or daily rhythm inherent in all biological systems may be causal for manifestations of Metabolic Syndrome (MetS), we sought to study variants of the human CLOCK gene and their correlation with features of obesity. Genetic assessment was performed in 1100 White Americans and dietary intakes were estimated from an approved food frequency questionnaire. Several CLOCK gene variations were significantly associated with obesity and individual components of MetS. For CLOCK variant rs4580704, persons carrying the less common version showed 31% less risk to develop diabetes (a component of MetS) and 46% less risk of suffering from hypertension (also a MetS component) than persons carrying the more common gene variant. A more detailed analysis showed that the protective effect of this gene variant on insulin sensitivity only became visible when monounsaturated-fatty-acid (MUFA) intake was higher than the average for this population. Another CLOCK variant, 3111 or rs1801260, showed different effects relating to intake of saturated fatty acids (SFA). The deleterious effect of gene variants on waist circumference was only found when SFA intake was above the average. In conclusion, CLOCK genetic variants interact with dietary fatty acids to modulate MetS components.
Technical Abstract: Background: Disruption of the circadian system may be causal for manifestations of Metabolic Syndrome (MetS). Objective: To study the associations of five CLOCK polymorphisms with MetS features considering fatty acid (FA) composition, from dietary and red-blood-cells (RBC) membrane sources. Design: 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. Anthropometric, biochemical measurements and genotypes were determined. Postprandial lipids and fatty acid (FA) composition of red blood-cells (RBC) membranes were analyzed. Results: CLOCK SNPs were significantly associated with obesity and individual components of MetS. For SNP rs4580704, minor allele carriers showed 31% less risk to develop diabetes and 46% less risk of suffering from hypertension than non-carriers. Monounsaturated-fatty-acids (MUFA) content of RBC membranes, particular oleic acid, changed according to CLOCK genetic variants (P<0.05). We identified significant gene-diet interactions associated to MetS at the CLOCK locus. By dichotomizing MUFA intake, we found different effects across rs4580704 genotypes for glucose (P=0.020) and insulin resistance (HOMA) (P= 0.026). The protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was higher than 13.2% of energy. We also found different effects across CLOCK 3111T>C genotypes for saturated fatty acid intake (% energy) (P=0.017). The deleterious effect of gene variants on waist circumference was only found with high SFA intakes (>11.8%). Conclusions: CLOCK polymorphisms interact with FAs to modulate MetS traits. Dietary source and membrane content of MUFAs are implicated in the relationship between alterations of circadian system and MetS.