The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects

Abstract

SUMMARY Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An association has been reported previously between a polymorphism (3111C), situated in the 3′‐untranslated region (3′‐UTR) of the circadian gene Clock and evening preference. In the present study, this polymorphism was assessed in: (1) 105 control subjects with defined diurnal preference, (2) 26 blind subjects with free‐running circadian rhythms and characterized with regard to circadian period (τ) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne‐Östberg questionnaire analysis, from which three subgroups were selected (evening, intermediate and morning preference). Data from sleep diaries completed by 90% of these subjects showed a strong correlation between preferred and estimated timings of sleep and wake. The mean timings of activities for the evening group were at least 2 h later than the morning group. Genetic analysis showed that, in contrast with the previously published finding, there was no association between 3111C and eveningness. Neither was there an association between 3111C and τ, nor a significant difference in 3111C frequency between the normal and delayed sleep phase syndrome groups. To assess the effect of this polymorphism on messenger RNA (mRNA) translatability, luciferase reporter gene constructs containing the two Clock polymorphic variants in their 3′‐UTR were transfected into COS‐1 cells and luciferase activity measured. No significant difference was observed between the two variants. These results do not support Clock 3111C as a marker for diurnal preference, τ, or delayed sleep phase syndrome in humans.

Distribution and heritability of diurnal preference (chronotype) in a rural Brazilian family-based cohort, the Baependi study

“…The general shift towards morningness in the Baependi population as compared to urban ones is shown in Figure 2, where the combined data from all Baependi volunteers are plotted against the combined data from two studies performed in London 14,20 as well as against data from residents of the city of São Paulo, collected through a web-based version of the validated Portuguese translation of the MEQ questionnaire. Figure 3 shows MEQ score in the combined population as a function of age.…”

Do Caucasian and Asian clocks tick differently?

“…Another typical example of differences between Caucasians and Asians is a polymorphism characterized by the change of a nucleotide T to C at position 3111 (T3111C) of the circadian gene CLOCK. Several studies have shown associations or not with circadian phenotypes, but in spite of the controversy about the effect of this polymorphism in circadian regulation, when one analyzes the allelic frequencies in these five different studies (4,6,(8)(9)(10) conducted in different laboratories, it is possible to observe that the intragroup allelic frequencies are similar in Caucasian or Asian studies, but different between the ethnic groups studied.…”

Identification of human Clock gene variants by denaturing high-performance liquid chromatography

“…Another polymorphism reported in the literature, 3092T/C (also known as 3111T/C) was reportedly associated with the diurnal preference of evening type in Caucasians (Katzberg et al 1998), but the association was not replicated (Robilliard et al 2002). There was also no association in a study of the SNP with major depression (Desan et al 2000).…”