Differences in circadian rhythmicity in CLOCK 3111T/C genetic variants in moderate obese women as assessed by thermometry, actimetry and body position

Authors: BANDIN, CRISTINA - Universidad De Murcia; MARTINEZ-NICOLAS1ANO, ANTONIO - Universidad De Murcia; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ROS, LUCAS - University Hospital Virgen De La Arrixaca Of Murcia; CASTELL, PEDRO - Universidad De Murcia; SILVENTE, TRINIDAD - University Hospital Reina Sofia; MADRID, JUAN ANTONIO - Universidad De Murcia; GARAULET, MARTA - Universidad De Murcia

Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2012
Publication Date: 8/1/2013
Publication URL: http://Differences in circadian rhythmicity in CLOCK 3111T/C genetic variants in moderate obese women as assessed by thermometry, actimetry and body position
Citation: Bandin, C., Martinez-Nicolas1ano, A., Ordovas, J.M., Ros, L.J., Castell, P., Silvente, T., Madrid, J., Garaulet, M. 2013. Differences in circadian rhythmicity in CLOCK 3111T/C genetic variants in moderate obese women as assessed by thermometry, actimetry and body position. International Journal of Obesity. 37(8):1044-1050.

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 related to obesity and weight loss. However, the mechanisms of these relations are not known. Therefore, the objective of this study was to determine, in free-living conditions, if the presence of one of such variants in the CLOCK gene, known as 3111T/C, was related to circadian disorders including poor sleep quality in overweight women. We measured series of relevant markers of circadian functionality during 8 consecutive days on 85 overweight women. Approximately half of the women were carrying the minor allele (C) for CLOCK 3111T/C SNP and the other half were TT carriers (major allele carriers). Both groups were matched for age, obesity parameters and energy intake. Our results show that TT women showed a more robust circadian rhythm than women with the C allele. In fact the presence of the C allele was characterized by significant circadian abnormalities. Moreover, C women were also less active, started their activities later in the morning and were sleepier during the day. In summary, the presence of a common genetic variant at the CLOCK gene was associated with chronodysruption and the potential for metabolic alterations and poor health. Our work supports the notion that identifying CLOCK genotypes in subjects may facilitate better disease prevention.

Technical Abstract: Genetics is behind our circadian machinery. CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C single-nucleotide polymorphism (SNP) has been previously related to obesity and weight loss. However, phenotypic association and functionality of CLOCK 3111 locus is still unknown. The aim of this study was to determine, in free-living conditions, if the presence of CLOCK 3111C in overweight women could be related to (a) circadian disorders, and (b) changes in sleep quality, to improve understanding of the previously demonstrated associations with obesity and reduced weight loss of the C carriers. Wrist temperature, actimetry and position (TAP) and TAP variables were measured as markers of circadian functionality during 8 consecutive days. A rest-activity and food diary was also completed, whereas sleep quality was determined by domiciliary polysomnography. We recruited 85 women who were overweight with body mass index (BMI) of 28.59±4.30'kg'm(-2) and age 43±12 years. From this sample, we found that 43 women were carrying the minor allele (C) for CLOCK 3111T/C SNP and 42 women were TT carriers (major allele carriers). Both groups of patients were matched for number, age, obesity parameters and energy intake. Compared with TT subjects, who showed more robust circadian rhythm profiles, patients with the C allele displayed significant circadian abnormalities: lower amplitude and greater fragmentation of the rhythm, a less stable circadian pattern and a significantly weakened circadian function, as assessed by the circadian function index (CFI). C subjects were also less active, started their activities later in the morning and were sleepier during the day, showing a delayed acrophase that characterizes 'evening-type' subjects. C genetic variants in CLOCK 3111T/C display a less robust circadian rhythm than TT and a delayed acrophase that characterizes 'evening-type' subjects. We support the notion that identifying CLOCK genotypes in patients may assist the therapist in characterization of the roots of the metabolic problem.