The CLOCK 3111T/C SNP is associated with morning gastric motility in healthy young women
Highlights
► We hypothesized that the CLOCK 3111T/C SNP is related to morning digestive activity. ► We measured gastric motility using electrogastrography (EGG) in 95 young women. ► C allele carriers manifested lower EGG frequency, suggesting slower gastric motility. ► This SNP was likely correlated with attenuated morning gastric motility.
Introduction
Various biological, physiological or behavioral processes with the day/night cycle including those associated with food digestion and absorption are subject to a circadian clock [1], [2]. In mammals, a central circadian clock is located within pacemaker neurons of the hypothalamic suprachiasmatic nucleus (SCN) [3]. Recent studies have shown that the majority of peripheral tissues also possess self-sustained clocks and in synchronization with the SCN via neural and humoral pathways, i.e., the brain SCN clock provides “standard time” for peripheral tissue clocks [4].
In the SCN as well as in peripheral organs, a series of clock genes (Cry, Per, CLOCK, Bmal 1) are expressed that show approximately 24-h cycles of transcription/translation [4]. The CLOCK, a positive element of autoregulatory feedback loop in the circadian clock [4], was first identified in a mutant mouse with altered circadian locomotor activity [5]. In animals, homozygous CLOCK mutant mice had an increased food intake during the light cycle (inactive period for mice) and developed metabolic syndrome [6]. In humans, the CLOCK 3111T/C single nucleotide polymorphism (SNP) was related to not only behavioral patterns such as evening preference, a shorter sleep duration [7], [8], and a delayed breakfast time [7], but also resistance against diet-induced weight loss [7]. These allele specific eating patterns raise a possibility that this SNP may affect the circadian regulation of gastrointestinal motility.
Indeed, new findings highlight the existence of clock genes within gastrointestinal epithelial cells [9], [10], suggesting a possible role for clock genes in circadian functions of the gastrointestinal tract through the modulation of organ-specific, clock-controlled genes [11]. As to intestinal motility, it has reported that most people have a bowel movement in the morning, and altered movements, such as diarrhea or constipation, are prevalent among shift workers or time-zone travelers [12]. However, it has not yet been fully understood whether weakened circadian system due to gene polymorphism affects motility of stomach.
The mechanical motility of the stomach is regulated by gastric electrical activity, which consists of rhythmic normal wave at a frequency of 3 cycles per min (cpm) delivered from pacemaker cells [13], [14], [15]. Because of non-invasive methods in which a cutaneous recording of gastric electrical activity is made from surface electrodes placed on the abdomen, electrogastrography (EGG) has gained popularity as a functional indicator of gastric motility [13], [14], [15]. The parameters calculated by means of EGG power spectral analysis, such as normal EGG powers (2–4 cpm) and dominant frequency (DF, a peak of the spectrum within the range of 1 to 9 cpm), have reported associations with gastric motility [13], [14], [15], [16], [17].
Additionally, the normal alternation of rest and activity is accompanied by a shift in the balance of sympathetic (SNS) and parasympathetic nervous system (PNS) activities, and this balance of the autonomic nervous system (ANS) is critically dependent on the output of central clock [18]. We therefore estimated the ANS activity by means of heart rate variability (HRV) power spectral analysis [19], [20], [21], [22]. The fluctuation of heart rate (HR) is modified by SNS and PNS. Thus, analyzing the HRV could safely and reliably measure the activities of both branches of the ANS.
Based on the hypothesis that the CLOCK 3111T/C SNP has adverse effects on the regulation of gastric motility, we designed to examine whether this SNP influences morning gastric motility in healthy young women.
Section snippets
Subjects
We studied 95 female university students (mean ± s.e., 19.6 ± 0.2 years) recruited from our campus. All subjects were non-smokers, free of any symptoms or medical history of gastrointestinal, cardiovascular, or any diseases that affect gastric motility and cardiovascular function and were not taking any medications. The subjects gave their written informed consent for the study, which was approved by the Ethics Committee of the University of Hyogo.
Experimental protocol
All subjects were asked to maintain their usual
Biological characteristics
Table 1 shows the biological characteristics of subjects by SNP of the CLOCK gene. The frequencies of T/T, T/C, and C/C genotypes of the CLOCK gene were 0.63, 0.36, and 0.01, respectively. The frequency of the C allele was 0.19. This value was similar to earlier Japanese reports [23], [24]. No significant deviation from Hardy–Weinberg equilibrium was observed.
To examine the effect of C allele, the subjects were divided into 2 groups focusing on with (T/C + C/C, n = 35) or without the C allele (T/T,
Discussion
In the present study, we examined the impact of the CLOCK 3111T/C SNP on morning gastric motility in healthy young women, and obtained intriguing findings. In C allele carriers, the DF of the waves significantly shifted towards the lower frequency as compared to T/T subjects, indicating slower gastric motility. Moreover, the normal power in C allele carriers tended to be lower than in T/T subjects. Thus, our data supported our hypothesis that the CLOCK 3111T/C SNP has adverse effects on the
Acknowledgments
We are grateful to all subjects for their cooperation. This study was supported by a grant-in-aid for Science Research from the Ministry of Education and Science of Japan (21500786).
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