title: The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects.
abstract: 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 (tau) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne-Ostberg 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 tau, 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, tau, or delayed sleep phase syndrome in humans.
authors.affiliation: Centre for Chronobiology, School of Biomedical and Life Sciences, University of Surrey, Guildford, UK.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Robilliard
authors.forename: Simon N
authors.initials: SN
authors.lastname: Archer
authors.forename: Josephine
authors.initials: J
authors.lastname: Arendt
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lockley
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hack
authors.forename: Judie
authors.initials: J
authors.lastname: English
authors.forename: Damien
authors.initials: D
authors.lastname: Leger
authors.forename: Marcel G
authors.initials: MG
authors.lastname: Smits
authors.forename: Adrian
authors.initials: A
authors.lastname: Williams
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Skene
authors.forename: Malcolm
authors.initials: M
authors.lastname: Von Schantz
mesh_terms: D000483:Alleles; D056926:CLOCK Proteins; D018929:Cell Culture Techniques; D002940:Circadian Rhythm / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012890:Sleep / Q000502:physiology*; D011795:Surveys and Questionnaires; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human