Circadian rhythm genes CLOCK and PER3 polymorphisms and morning gastric motility in humans

Abstract

Background: Clock genes regulate circadian rhythm and are involved in various physiological processes, including digestion. We therefore investigated the association between the CLOCK 3111T/C single nucleotide polymorphism and the Period3 (PER3) variable-number tandem-repeat polymorphism (either 4 or 5 repeats 54 nt in length) with morning gastric motility.

Methods: Lifestyle questionnaires and anthropometric measurements were performed with 173 female volunteers (mean age, 19.4 years). Gastric motility, evaluated by electrogastrography (EGG), blood pressure, and heart rate levels were measured at 8:30 a.m. after an overnight fast. For gastric motility, the spectral powers (% normal power) and dominant frequency (DF, peak of the power spectrum) of the EGG were evaluated. The CLOCK and PER3 polymorphisms were determined by polymerase chain reaction (PCR) restriction fragment length polymorphism analysis.

Results: Subjects with the CLOCK C allele (T/C or C/C genotypes: n = 59) showed a significantly lower DF (mean, 2.56 cpm) than those with the T/T genotype (n = 114, 2.81 cpm, P < 0.05). Subjects with the longer PER3 allele (PER34/5 or PER35/5 genotypes: n = 65) also showed a significantly lower DF (2.55 cpm) than those with the shorter PER34/4 genotype (n = 108, 2.83 cpm, P < 0.05). Furthermore, subjects with both the T/C or C/C and PER34/5 or PER35/5 genotypes showed a significantly lower DF (2.43 cpm, P < 0.05) than subjects with other combinations of the alleles (T/T and PER34/4 genotype, T/C or C/C and PER34/4 genotypes, and T/T and PER34/5 or PER35/5 genotypes).

Conclusions: These results suggest that minor polymorphisms of the circadian rhythm genes CLOCK and PER3 may be associated with poor morning gastric motility, and may have a combinatorial effect. The present findings may offer a new viewpoint on the role of circadian rhythm genes on the peripheral circadian systems, including the time-keeping function of the gut.

Fig 1. EGG power spectrum analysis results.

Typical sets of raw EGG waves (top of each figure) and the corresponding power spectral data (bottom of each figure) obtained from a T/T and PER3 ^4/4 (A) and a T/C and PER3 ^4/5 genotype subject (B). By visual inspection, in the T/C and PER3 ^4/5 genotype subject, the DF of the waves was diminished and shifted toward the slower frequency compared to the T/T and PER3 ^4/4 genotype subject.

Fig 2. The resting HR of the four combined polymorphic types.

Subjects with both T/C or C/C and PER3 ^4/5 or PER3 ^5/5 genotypes displayed the lowest resting HR values among the four groups. Additionally, there was a significant difference in the resting HR between the T/T and PER3 ^4/4 genotype and T/C or C/C and PER3 ^4/5 or PER3 ^5/5 genotypes (ANOVA followed by post-hoc Tukey’s test).

Fig 3. The DF of the four combined polymorphic types.

Subjects with both T/C or C/C and PER3 ^4/5 or PER3 ^5/5 genotypes displayed the lowest DF values among the four groups, suggesting the slowest gastric motility. Additionally, there was a significant difference in the DF between the T/T and PER3 ^4/4 genotype and T/C or C/C and PER3 ^4/5 or PER3 ^5/5 genotypes (ANOVA followed by post-hoc Tukey’s test).