CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control

Abstract

Background/objectives: Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control.

Subjects/methods: We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power.

Results: In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015).

Conclusions: The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control.

Trial registration: ClinicalTrials.gov NCT02829619.

Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest

Figures

Fig. 1

A representative heartbeat recording of a TT carrier. The grey shaded areas indicate subject’s habitual sleep episodes.

Fig. 2

Daily pattern of heart rate variability (HRV). Shown are (means±SE) group averages of mean RR, SDNN (a marker for overall HRV), pNN50 (a time-domain marker of cardiac vagal modulation), and HF (a frequency-domain marker of cardiac vagal modulation). The log transform of HF (lnHF) was used to HF to ensure a normal distribution. Solid curves are the fits based on cosinor mixed models.

Fig. 3

Effect of the genetic variant CLOCK 3111T/C on the amplitude of daily heart rate variability rhythm. The rhythms of HRV indices (mean RR, SDNN, pNN50, HF) were estimated using 24-h sinusoids and 12-h harmonics. The log transform of HF (lnHF) was used to HF to ensure a normal distribution. (A–D) Group averages (SE) of the amplitudes/coefficients of the 24-h components (A), the peak-trough amplitudes of the overall fits (B), the peak values (C) and the trough values (D). Significant group differences are indicated by * (p<0.05), ** (p<0.01), or *** (p<0.0001).

Fig. 4

Effect of the genetic variant CLOCK 3111T/C on the association between weight loss and daily heart rate variability rhythm. To demonstrate the weight-rhythm association, the 24-h components in the daily rhythms of heart rate variability indices (A–F) and the corresponding amplitudes (G–I) in five categories of weight loss (i.e., <5.3kg, 5.3–7.4 kg, 7.4–9.7 kg, 9.7–11.9kg, and >11.9 kg) were shown. Note that there were no C carriers in the category of >11.9 kg. Results were based on mixed models with weight loss (a continuous variable), group, coefficients of 24-h components, and their interactions (weigh loss x 24-h coefficients) as the fixed effects and subject as a random effect.