Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome

Authors: GARCIA-RIOS, ANTIONIO - Universidad De Cordoba; GOMEZ-DELGADO, FRANCISCO - Universidad De Cordoba; GARAULET, MARTA - Universidad De Murcia; ALCALA-DIAZ, JEAN - Universidad De Cordoba; DELGADO-LISTA, FRANCISCO - Universidad De Cordoba; MARIN, CARMEN - Universidad De Cordoba; RANGUEL-ZUNIGA, ORIOL - Universidad De Cordoba; RODRIGUEZ-CANTALEJO, FERNANDO - Universidad De Cordoba; GOMEZ-LUNA, PURIFICACION - Universidad De Cordoba; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; PEREZ-JIMENEZ, FRANCISCO - Universidad De Cordoba; LOPEZ-MIRANDA, JOSE - Universidad De Cordoba; PEREZ-MARTINEZ, PABLO - Universidad De Cordoba

Submitted to: Chronobiology International
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/6/2013
Publication Date: 4/1/2014
Citation: Garcia-Rios, A., Gomez-Delgado, F., Garaulet, M., Alcala-Diaz, J., Delgado-Lista, F., Marin, C., Ranguel-Zuniga, O., Rodriguez-Cantalejo, F., Gomez-Luna, P., Ordovas, J.M., Perez-Jimenez, F., Lopez-Miranda, J., Perez-Martinez, P. 2014. Beneficial effect of CLOCK gene polymorphism rs1801260 in combination with low-fat diet on insulin metabolism in the patients with metabolic syndrome. Chronobiology International. 31(3):401-408.

Interpretive Summary: A circadian rhythm is any biological process that displays an internally regulated, repetitive variation of time of about 24 hours. A circadian (or biological) clock drives this rhythm. Circadian rhythmicity is present in the sleeping and feeding patterns of human beings. There are also clear patterns of core body temperature, brain wave activity, hormone production, cell regeneration and other biological activities. Therefore, maintaining proper synchrony among all these functions is essential for the health of the individual. The molecular basis of our biological clock relates to the expression of the clock genes. Thus, we have previously shown that variation at the CLOCK (Circadian Locomotor Output Cycles Kaput) is associated with lifestyle-related conditions such as obesity, metabolic syndrome (MetS) and cardiovascular disease. The objective of this study was to find out whether habitual consumption of a low-fat diet, compared with a Mediterranean diet enriched with olive oil, modulates the associations between common CLOCK DNA sequence variations occurring commonly within a population (single nucleotide polymorphisms - SNPs) (rs1801260, rs3749474 and rs4580704) and fat and sugar metabolism-related traits among MetS patients. Plasma lipid (fat) and insulin concentrations, indexes related with insulin resistance and quantitative insulin sensitivity check index (QUICKI)) and CLOCK SNPs were determined in 475 MetS subjects participating in the CORDIOPREV clinical trial. Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet versus low-fat diet). We found significant gene-diet interactions between rs1801260 SNP and the dietary pattern for insulin concentrations, HOMA-IR and QUICKI. Specifically, after 12 months of low-fat intervention, subjects who were homozygous (having identical pairs of genes for any given pair of hereditary characteristics) for the major allele (TT) displayed lower plasma insulin concentrations, lower insulin resistance and higher insulin sensitivity compared with carriers of the minor allele C (TC + CC). In contrast, in the Mediterranean intervention group no significant differences were found between CLOCK genotypes after 12 months of treatment. Our data support the notion that a chronic consumption of a healthy diet may play a contributing role in triggering glucose metabolism by interacting with the CLOCK gene in MetS patients. Our work supports the notion that identifying CLOCK genotypes in subjects may facilitate better disease prevention.

Technical Abstract: Genetic variation at the Circadian Locomotor Output Cycles Kaput (CLOCK) locus has been associated with lifestyle-related conditions such as obesity, metabolic syndrome (MetS) and cardiovascular diseases. In fact, it has been suggested that the disruption of the circadian system may play a causal role in manifestations of MetS. The aim of this research was to find out whether habitual consumption of a low-fat diet, compared with a Mediterranean diet enriched with olive oil, modulates the associations between common CLOCK single nucleotide polymorphisms (SNPs) (rs1801260, rs3749474 and rs4580704) and lipid and glucose-related traits among MetS patients. Plasma lipid and insulin concentrations, indexes related with insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)) and CLOCK SNPs were determined in 475 MetS subjects participating in the CORDIOPREV clinical trial (NCT00924937). Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% monounsaturated fatty acids (MUFA)) versus low-fat diet (28% fat, 12% MUFA)). We found significant gene-diet interactions between rs1801260 SNP and the dietary pattern for insulin concentrations (p = 0.009), HOMA-IR (p = 0.014) and QUICKI (p = 0.028). Specifically, after 12 months of low-fat intervention, subjects who were homozygous for the major allele (TT) displayed lower plasma insulin concentrations (p = 0.032), lower insulin resistance (HOMA-IR; p = 0.027) and higher insulin sensitivity (QUICKI; p = 0.024) compared with carriers of the minor allele C (TC + CC). In contrast, in the Mediterranean intervention group a different trend was observed although no significant differences were found between CLOCK genotypes after 12 months of treatment. Our data support the notion that a chronic consumption of a healthy diet may play a contributing role in triggering glucose metabolism by interacting with the rs1801260 SNP at CLOCK gene locus in MetS patients. Due to the complex nature of gene-environment interactions, dietary adjustment in subjects with the MetS may require a personalized approach.