The 3111T/C polymorphism interacts with stressful life events to influence patterns of sleep in females

Genetic variations in clock-relevant genes have been investigated in relation to sleep abnormalities, both in healthy populations and in mood-disorder patients with inconsistent results. Environmental influences may moderate associations between genes and phenotype. The authors examined the CLOCK 3111T/C polymorphism and several variants within the PER3 gene and their possible interaction with stressful life events in a group of female volunteers (n = 415). Gene-environment (G × E) interactions and gene main effects were investigated on depressive symptoms using the Beck Depression Inventory and on change of sleep patterns (Item 16). Results showed a G × E interaction on alteration of sleeping pattern: the 3111C homozygous genotype reported greater disruption in sleep pattern after the experience of stressful life events. Within the PER3 gene, one G × E interaction was observed with rs228642 on sleep change. These findings show that the 3111T/C polymorphism is not associated with depressive symptoms, but only with symptoms of sleep change in the case of prior stressful life experiences. The combination of a sensitive genotype (3111C/C) and environmental stress increases vulnerability to circadian rhythm disruption in females.     

3111T/C CLOCK GENE POLYMORPHISM IS NOT ASSOCIATED WITH SLEEP DISTURBANCES IN UNTREATED DEPRESSED PATIENTS

Sleep patterns, frequently altered in depression, have been hypothesized to be under genetic control. The circadian locomotor output cycles kaput (CLOCK) T3111C variant has been studied in association with sleep disturbances in depressed patients. The aim of this study was to investigate possible effects of T3111C CLOCK on insomnia, daytime sleepiness, sleep quality, and depression severity in a sample of 100 major depressive disorder patients. Inclusion criteria were: major depressive disorder, drug-free for any antidepressant and/or benzodiazepines for at least four weeks previously to the study, and a minimum score of >17 on the Hamilton Rating Scale for Depression. The Morningness–Eveningness Questionnaire, Epworth Sleepiness Scale, Athens Insomnia Scale, and Pittsburgh Sleep Quality Index were applied. No significant difference was found concerning genotype or allele groups and Hamilton Rating Scale for Depression items or clusters. No difference was found between genotypes and comorbidity, chronotype distribution, Epworth Sleepiness Scale, Athens Insomnia Scale, or Pittsburgh Sleep Quality Index total scores. Overall, the present findings did not support the hypothesis of an effect of the T3111C CLOCK variant on sleep disturbances in major depressive disorder. Further analysis of clock machinery will clarify the contribution of clock genes to the maintenance of mental health. (Author correspondence: alessandro.serretti@unibo.it)     

Association Study of a Variable-Number Tandem Repeat Polymorphism in the Clock Gene PERIOD3 and Chronotype in Norwegian University Students

Circadian rhythms are endogenously generated cycles involving physiological parameters, such as core body temperature, hormone levels, blood pressure, sleep, and metabolism, with a period length of around 24?h. The circadian clock in mammals is regulated by a set of clock genes that are functionally linked together, and polymorphisms in clock genes could be associated with differences in circadian rhythms. A variable-number tandem repeat (VNTR) in the human clock gene PERIOD3 (PER3) has been suggested to correlate with a morning (lark) versus evening (owl) chronotype as well as with the circadian rhythm sleep disorder “delayed sleep phase disorder” (DSPD). The authors examined 432 healthy Norwegian university students in search of further support for an association between the PER3 polymorphism and diurnal preference. The Horne-Östberg Morningness-Eveningness Questionnaire (MEQ) and Preferences Scale (PS) were used to evaluate subjective chronotype. DNA samples were genotyped with respect to the 4-repeat and 5-repeat alleles of the VNTR PER3 polymorphism, and the genotype distribution was 192 (4-4), 191 (4-5), and 49 (5-5). The authors estimated that the power to detect an association of the 4-allele with preference for morningness or eveningness was 75%. The authors found no association between the PER3 clock gene and chronotype, indicating that the proposed role of PER3 needs further clarification. (Author correspondence: teresa.osland@med.uib.no)     

The CLOCK Gene and Mood Disorders: A Case-Control Study and Meta-analysis

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n?=?867) and MDD (n?=?139) compared to controls (n?=?889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p_BP?=?.605 and global p_MDD?=?.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders. (Author correspondence: tarok@fujita-hu.ac.jp)     

Sleep,Diurnal Preference,Health, and Psychological Well-being: A Prospective Single-Allelic-Variation Study

Individual differences in sleep and diurnal preference associate with physical and mental health characteristics, but few genetic determinants of these differences have been identified. A variable number tandem repeat (VNTR) polymorphism in the PERIOD3 (PER3) gene (rs57875989) has been reported to associate with diurnal preference, i.e., preferred timing of waking and sleep. Here, the authors investigate in a prospective single-candidate genetic variant study whether allelic variation for this polymorphism associates also with reported actual sleep timing and sleep duration, as well as psychological and health measures. Six hundred and seventy-five subjects, aged 20 to 35 yrs, completed questionnaires to assess sleep and psychological and health characteristics and were genotyped for the PER3 VNTR. Homozygosity for the longer allele (PER3^5/5) of the VNTR was associated with increased morning preference, earlier wake time and bedtime, and reduced daytime sleepiness. Separate analyses of work and rest days demonstrated that the increase in time in bed during rest days was greatest in PER3^5/5 homozygotes. PER3 genotype modified the effects of sleep timing and duration on fluid intelligence and body mass index. Genotype was not associated with physical or psychological characteristics as assessed by the SF-36 Health Questionnaire, the General Health Questionnaire, the Big Five Inventory, the Behavioral Inhibition System–Behavioral Activation System scales, and the Positive and Negative Affect Scale, even though these measures varied significantly with diurnal preference as assessed by the Morningness-Eveningness Questionnaire. Whereas diurnal preference also predicts mental health and psychological characteristics, as well as sleep timing, the PER3 VNTR specifically affects measures of sleep timing and may also modify the effects of sleep on health outcome measures. (Author correspondence: a.lazar@surrey.ac.uk)     

Time-of-Day Mediates the Influences of Extended Wake and Sleep Restriction on Simulated Driving

Although a nonlinear time-of-day and prior wake interaction on performance has been well documented, two recent studies have aimed to incorporate the influences of sleep restriction into this paradigm. Through the use of sleep-restricted forced desynchrony protocols, both studies reported a time-of-day?×?sleep restriction interaction, as well as a time-of-day?×?prior wake?×?sleep dose three-way interaction. The current study aimed to investigate these interactions on simulated driving performance, a more complex task with ecological validity for the problem of fatigued driving. The driving performance of 41 male participants (mean?±?SD: 22.8 ±2.2 yrs) was assessed on a 10-min simulated driving task with the standard deviation of lateral position (SDLAT) measured. Using a between-group design, participants were subjected to either a control condition of 9.33?h of sleep/18.66?h of wake, a moderate sleep-restriction (SR) condition of 7?h of sleep/21?h of wake, or a severe SR condition of 4.66?h of sleep/23.33?h of wake. In each condition, participants were tested at 2.5-h intervals after waking across 7?×?28-h d of forced desynchrony. Driving sessions occurred at nine doses of prior wake, within six divisions of the circadian cycle based on core body temperature (CBT). Mixed-models analyses of variance (ANOVAs) revealed significant main effects of time-of-day, prior wake, sleep debt, and sleep dose on SDLAT. Additionally, significant two-way interactions of time-of-day?×?prior wake and time-of-day?×?sleep debt, as well as significant three-way interactions of time-of-day?×?prior wake?×?sleep debt and time-of-day?×?sleep debt?×?sleep dose were observed. Although limitations such as the presence of practice effects and large standard errors are noted, the study concludes with three findings. The main effects demonstrate that extending wake, reducing sleep, and driving at poor times of day all significantly impair driving performance at an individual level. In addition to this, combining either extended wake or a sleep debt with the early morning hours greatly decreases driving performance. Finally, operating under the influence of a reduced sleep dose can greatly decrease performance at all times of the day. (Author correspondence: raymond.matthews@unisa.edu.au)     

Chronotype and PERIOD3 Variable Number Tandem Repeat Polymorphism in Individual Sports Athletes

A link between diurnal preference and a variable number tandem-repeat (VNTR) polymorphism in the PERIOD3 gene (PER3) has been demonstrated: the longer PER3⁵ and shorter PER3⁴ alleles with preferences for mornings and evenings, respectively. As many competitive events in South Africa for individual athletes are scheduled for the early mornings, we hypothesized that this might favor those athletes with a preference for morning activities. Self-selected white, male cyclists (CYC, n = 125), runners (RUN, n = 120) and Ironman triathletes (IM, n = 287) of European descent were compared with a control population of active, non-competitive individuals (CON, n = 96). The chronotypes of all CYC, RUN and CON participants and a sub-sample of the IM group (n = 49) were assessed using the Horne–Östberg Morningness–Eveningness Questionnaire, and the PER3 VNTR genotype for each participant was determined. The athlete groups contained more morning-type individuals than the CON group (CYC: 72%, n = 90; RUN: 67%, n = 80; IM: 59%, n = 29; CON: 41%, n = 39; p < .001). The prevalence of the PER3⁵ allele was greater in the athlete groups (CYC: 61%, n = 152; RUN: 58%, n = 132; IM: 56%, n = 324; CON: 38%, n = 76; p < .001), and more athletes were genotyped as PER3^5/5 than CON individuals (CYC: 41%, n = 51; RUN: 23%, n = 26; IM: 28%, n = 81, CON: 9%, n = 8; p < .001). A strong relationship between chronotype and PER3 VNTR genotype was observed (p < .001). Finally, the time of day at which the athletes preferred to train was related to their chronotype (p < .001). This is the first study of its kind in a South African sporting population, and the results have not yet been replicated. These data suggest that white males of European descent participating in individual endurance sports in South Africa are more likely to be morning types. Furthermore, the PER3 VNTR may be one of the factors contributing to this observation. (Author correspondence: laura.roden@uct.ac.za)     

T3111C CLOCK SINGLE NUCLEOTIDE POLYMORPHISM AND MOOD DISORDERS: A META-ANALYSIS

It has been hypothesized that abnormalities in the molecular clock underlie the development of mood disorders, in the direction of higher prevalence in individuals with a reduced flexibility to adapt to important regulations of mood in response to changes in seasons, stress levels, sleep schedules, and time zones. In particular, a T/C change (rs1801260) at the 3111 position of the circadian locomotor output cycles kaput (CLOCK) gene has been explored in psychiatry disorders. This meta-analysis has been undertaken to investigate the association between rs1801260 and both mood disorders and depression severity, shedding light on previous controversial results and providing better power to detect smaller effect sizes. PubMed and ISI databases were searched for studies focused on the association between rs1801260 and mood disorders spectrum. Quality of studies was assessed. We found no association between CLOCK genotypes and mood disorders, even when we separately investigated ethnical homogeneous or unipolar disorder studies. No association was found regarding severity of depression either. The methodological quality of the studies has been found to be medium-high. Our meta-analysis shows no association between rs1801260 and mood disorders (as a complete phenotype) or depression severity and points out the necessity of further research in order to better understand the underlying biological machinery of circadian dysfunction in subjects affected by mood disorders. (Author correspondence: alessandro.serretti@unibo.it)     

Clock Polymorphisms and Circadian Rhythms Phenotypes in a Sample of the Brazilian Population

A Clock polymorphism T to C situated in the 3′ untranslated region (3′‐UTR) has been associated with human diurnal preference. At first, Clock 3111C had been reported as a marker for evening preference. However these data are controversial, and data both corroborating and denying them have been reported. This study hypothesizes that differences in Clock genotypes could be observed if extreme morning‐type subjects were compared with extreme evening‐type subjects, and the T3111C and T257G polymorphisms were studied. The possible relationship between both polymorphisms and delayed sleep phase syndrome (DSPS) was also investigated. An interesting and almost complete linkage disequilibrium between the polymorphisms T257G in the 5′ UTR region and the T3111C in the 3′ UTR region of the Clock gene is described. Almost always, a G in position 257 corresponds to a C in position 3111, and a T in position 257 corresponds to a T in position 3111. The possibility of an interaction of these two regions in the Clock messenger RNA structure that could affect gene expression was analyzed using computer software. The analyses did not reveal an interaction between those two regions, and it is unlikely that this full allele correspondence affects Clock gene expression. These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). These controversial data could result from the possible effects of latitude and clock genes interaction on circadian phenotypes.     

Circadian regulation gene polymorphisms are associated with sleep disruption and duration,and circadian phase and rhythm in adults with HIV

Genes involved in circadian regulation, such as circadian locomotor output cycles kaput [CLOCK], cryptochrome [CRY1] and period [PER], have been associated with sleep outcomes in prior animal and human research. However, it is unclear whether polymorphisms in these genes are associated with the sleep disturbances commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thus, the purpose of this study was to describe polymorphisms in selected circadian genes that are associated with sleep duration or disruption as well as the sleep–wake rhythm strength and phase timing among adults living with HIV/AIDS. A convenience sample of 289 adults with HIV/AIDS was recruited from HIV clinics and community sites in the San Francisco Bay Area. A wrist actigraph was worn for 72?h on weekdays to estimate sleep duration or total sleep time (TST), sleep disruption or percentage of wake after sleep onset (WASO) and several circadian rhythm parameters: mesor, amplitude, the ratio of mesor to amplitude (circadian quotient), and 24-h autocorrelation. Circadian phase measures included clock time for peak activity (acrophase) from actigraphy movement data, and bed time and final wake time from actigraphy and self-report. Genotyping was conducted for polymorphisms in five candidate genes involved in circadian regulation: CLOCK, CRY1, PER1, PER2 and PER3. Demographic and clinical variables were evaluated as potential covariates. Interactions between genotype and HIV variables (i.e. viral load, years since HIV diagnosis) were also evaluated. Controlling for potentially confounding variables (e.g. race, gender, CD4+ T-cell count, waist circumference, medication use, smoking and depressive symptoms), CLOCK was associated with WASO, 24-h autocorrelation and objectively-measured bed time; CRY1 was associated with circadian quotient; PER1 was associated with mesor and self-reported habitual wake time; PER2 was associated with TST, mesor, circadian quotient, 24-h autocorrelation and bed and wake times; PER3 was associated with amplitude, 24-h autocorrelation, acrophase and bed and wake times. Most of the observed associations involved a significant interaction between genotype and HIV. In this chronic illness population, polymorphisms in several circadian genes were associated with measures of sleep disruption and timing. These findings extend the evidence for an association between genetic variability in circadian regulation and sleep outcomes to include the sleep–wake patterns experienced by adults living with HIV/AIDS. These results provide direction for future intervention research related to circadian sleep–wake behavior patterns.     

Genomic models with genotype × environment interaction for predicting hybrid performance: an application in maize hybrids

Key message

A new genomic model that incorporates genotype?×?environment interaction gave increased prediction accuracy of untested hybrid response for traits such as percent starch content, percent dry matter content and silage yield of maize hybrids.

Abstract

The prediction of hybrid performance (HP) is very important in agricultural breeding programs. In plant breeding, multi-environment trials play an important role in the selection of important traits, such as stability across environments, grain yield and pest resistance. Environmental conditions modulate gene expression causing genotype?×?environment interaction (G?×?E), such that the estimated genetic correlations of the performance of individual lines across environments summarize the joint action of genes and environmental conditions. This article proposes a genomic statistical model that incorporates G?×?E for general and specific combining ability for predicting the performance of hybrids in environments. The proposed model can also be applied to any other hybrid species with distinct parental pools. In this study, we evaluated the predictive ability of two HP prediction models using a cross-validation approach applied in extensive maize hybrid data, comprising 2724 hybrids derived from 507 dent lines and 24 flint lines, which were evaluated for three traits in 58 environments over 12 years; analyses were performed for each year. On average, genomic models that include the interaction of general and specific combining ability with environments have greater predictive ability than genomic models without interaction with environments (ranging from 12 to 22%, depending on the trait). We concluded that including G?×?E in the prediction of untested maize hybrids increases the accuracy of genomic models.

     

Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population

A Clock polymorphism T to C situated in the 3' untranslated region (3'-UTR) has been associated with human diurnal preference. At first, Clock 3111C had been reported as a marker for evening preference. However these data are controversial, and data both corroborating and denying them have been reported. This study hypothesizes that differences in Clock genotypes could be observed if extreme morning-type subjects were compared with extreme evening-type subjects, and the T3111C and T257G polymorphisms were studied. The possible relationship between both polymorphisms and delayed sleep phase syndrome (DSPS) was also investigated. An interesting and almost complete linkage disequilibrium between the polymorphisms T257G in the 5' UTR region and the T3111C in the 3' UTR region of the Clock gene is described. Almost always, a G in position 257 corresponds to a C in position 3111, and a T in position 257 corresponds to a T in position 3111. The possibility of an interaction of these two regions in the Clock messenger RNA structure that could affect gene expression was analyzed using computer software. The analyses did not reveal an interaction between those two regions, and it is unlikely that this full allele correspondence affects Clock gene expression. These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). These controversial data could result from the possible effects of latitude and clock genes interaction on circadian phenotypes.     

Allelic Variants Interaction of CLOCK Gene and G‐Protein β3 Subunit Gene with Diurnal Preference

The 3111 C/T single nucleotide polymorphism (SNP) in the CLOCK gene and the 825C/T SNP in the G‐protein β3 subunit gene (GNB3) have been reported to influence diurnal preference. This study has attempted to characterize the association between the CLOCK gene and GNB3 polymorphisms and diurnal preference in healthy Korean college students. All subjects completed the 13‐item Composite Scale for Morningness (CSM). The interaction between the 3111 C/T SNP in the CLOCK gene and the 825 C/T SNP in the GNB3 gene significantly influenced diurnal preference, according to the CSM Performance subscore (F=10.94, p=0.001). However, when the different polymorphisms of the two genes were analyzed independently, no direct correlations with diurnal preference were detected. The CLOCK gene 3111 C/T SNP and GNB3 gene 825 C/T SNP were found to manifest a gene‐gene interaction that affects diurnal preference.     

CIRCADIAN STUDY OF DECOMPRESSION SICKNESS SYMPTOMS AND RESPONSE-ASSOCIATED VARIABLES IN RATS

In order to study circadian rhythms and decompression sickness (DCS), we determined: 1) the baseline circadian time structure in noncompressed rats of potential response variables to compression/decompression (C/D), and 2) whether rats subjected to C/D display a circadian time-dependent difference in inflammatory response intensity and biological tolerance. Subgroups of male rats, standardized to a 12?h light/12?h dark schedule, were evaluated every 4?h over 24?h after they were either compressed to 683?kPa (group E) or remained at sea level (group C). During 60?min recovery, evaluation included gross DCS symptoms and pulmonary edema in all E rats, and cell counts, nitric oxide, protein, thromboxane B_2, and leukotriene E₄ levels in survivors. Chi-square, ANOVA, and 24?h cosinor analyses were used to test for time-of-day effects. C/D exposures near the end of dark/activity or during light/resting were generally better tolerated, with lowest signs of DCS symptoms and lowest responses by most of the variables monitored. More deaths were observed in the first half of the dark/activity span. Of the 16 subsets of inflammatory-associated variables, overall increases were observed in 13 and decreases in 2. Significant or borderline significant circadian time effects were found in 14 variables in group C, 12 variables in group E, and 13 variables in response (E%C). Thus, nearly all baseline indices of DCS demonstrated circadian time-dependencies in the sea-level exposed control rats (group C), and nearly all were modified by the circadian time of C/D. Such time-of-day effects of DCS are potentially relevant to the operational concerns of occupations involving decompression exposures and the investigation of prevention and treatment intervention strategies of DCS. (Author correspondence: Bruce.D.Butler@uth.tmc.edu).     

Clock genes beyond the clock: CLOCK genotype biases neural correlates of moral valence decision in depressed patients

Gene polymorphisms in the mammalian biological clock system influence individual rhythms. A single nucleotide polymorphism (SNP) in the 3' flanking region of CLOCK (3111 T/C; rs1801260) influenced diurnal preference in healthy humans and caused sleep phase delay and insomnia in patients affected by bipolar disorder. Genes of the biological clock are expressed in many brain structures other than in the 'master clock' suprachiasmatic nuclei. These areas, such as cingulate cortex, are involved in the control of many human behaviors. Clock genes could then bias 'nonclock' functions such as information processing and decision making. Thirty inpatients affected by a major depressive episode underwent blood oxygen–level dependent (BOLD) functional magnetic resonance imaging (fMRI). The cognitive activation paradigm was based on a go/no-go task. Morally connoted words were presented. Genotyping of CLOCK was performed for each patients. We measured activity levels through actimetry during the day before the fMRI study. CLOCK 3111 T/C SNP was associated with activity levels in the second part of the day, neuropsychological performance and BOLD fMRI correlates (interaction of genotype and moral valence of the stimuli). Our results support the hypothesis that individual clock genotype may influence several variables linked with human behaviors in normal and psychopathological conditions.     

ASSOCIATIONS BETWEEN CHRONOTYPE,SLEEP QUALITY,SUICIDALITY, AND DEPRESSIVE SYMPTOMS IN PATIENTS WITH MAJOR DEPRESSION AND HEALTHY CONTROLS

Research interest concerning associations between sleep characteristics and suicidality in psychopathology has been growing. However, possible linkages of suicidality to sleep characteristics in terms of sleep quality and chronotypes among depressive patients have not been well documented. In the current study, the authors investigated the possible effects of sleep quality and chronotype on the severity of depressive symptoms and suicide risk in patients with depressive disorder and healthy controls. The study was conducted on 80 patients clinically diagnosed with major depression and 80 healthy subjects who were demographically matched with the patient group. All participants completed a questionnaire package containing self-report measures, including the Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Morningness–Eveningness Questionnaire (MEQ), and Suicide Ideation Scale (SIS), and subjects were interviewed with the suicidality section of the Mini-International Neuropsychiatric Interview (MINI). Results are as follows: (a) logistic regression analyses revealed that poor sleep quality and depression symptom severity significantly predicted onset of major depression; (b) morningness-type circadian rhythm may play as a significant relief factor after onset of major depression; (c) sleep variables of chronotype and sleep quality did not significantly predict suicide ideation after controlling for depressive symptoms in the major depression group; and (d) suicide ideation and poor sleep quality were antecedents of depression symptom severity in patients with major depression, and in healthy controls. Findings are discussed under the theoretical assumptions concerning possible relations between chronotype, sleep quality, depression, and suicidality. (Author correspondence: dryavuzselvi@yahoo.com)     

GENE-GENE INTERACTION BETWEEN SEROTONIN TRANSPORTER (SLC6A4) AND CLOCK MODULATES THE RISK OF METABOLIC SYNDROME IN ROTATING SHIFTWORKERS

Serotonergic neurotransmission and the master circadian CLOCK gene are physiological modulators of the circadian system. In addition, both are involved in the physiopathology of metabolic syndrome (MS). The authors sought to examine the potential effect of the gene-gene interaction between the functional 44-bp insertion/deletion polymorphism in the promoter region (serotonin-transporter-linked promoter region polymorphism or 5-HTTLPR) of the serotonin transporter gene (SLC6A4) and common variants of the gene CLOCK on the genetic risk underlying MS of shift-workers. To test this hypothesis, 856 men were studied; 518 dayworkers were compared with 338 rotating shiftworkers. Medical history, health examination including anthropometric and arterial blood pressure measurements, a questionnaire on health-related behaviors, and biochemical determinations were obtained from every participant. 5-HTTLPR genotypes were determined using polymerase chain reaction followed by gel electrophoresis. Six tag single-nucleotide polymorphisms (SNPs) in the CLOCK gene with a minor allele frequency >10 % (rs1554483 C/G, rs11932595 A/G, rs4580704 C/G, rs6843722 A/C, rs6850524 C/G, and rs4864548 A/G), encompassing 117 kb of chromosome 4 and representing 115 polymorphic sites (r²?>?.8), were genotyped. A significant interaction between the 5-HTTLPR variant and the haplotype rs1554483–rs4864548 of the CLOCK gene was detected for diastolic (p?=?.0058) and systolic blood pressure (p?=?.0014), arterial hypertension (p?=?.033), plasma triglycerides levels (p?=?.033), and number of MS components (p?=?.01). In all these cases, the higher values were observed in rotating shiftworkers homozygous for the SLC6A4 S allele and carrying the haplotype composed by the CLOCK rs1554483 G and rs4864548 A variants. In conclusion, these data suggest a potential interaction (epistatic effect) of serotonin transporter and CLOCK gene variation on the genetic susceptibility to develop MS by rotating shiftworkers. (Author correspondence: cpirola@ciudad.com.ar or pirola.carlos@lanari.fmed.uba.ar)     

EVENING PREFERENCE IS RELATED TO THE INCIDENCE OF DEPRESSIVE STATES INDEPENDENT OF SLEEP-WAKE CONDITIONS

Although evening preference has recently been identified as a risk factor for depression, it has not been substantiated whether evening preference is a direct risk factor for depressive states, or if it is associated secondarily through other factors, such as delayed sleep timing and shortened sleep duration. The objective of this study is to investigate associations in Japanese adult subjects between evening preference and incidence of depressive states, adjusting for various sleep parameters related to depressive states. The Morningness-Eveningness Questionnaire (MEQ), the Pittsburgh Sleep Quality Index (PSQI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were administered to 1170 individuals (493 males/677 females; mean and range 38.5 and 20–59 yrs) to assess their diurnal preferences, sleeping states, and presence of depression symptoms. Subjects were classified into five chronotypes based on MEQ scores. Evening preference was associated with delayed sleep timing, shortened sleep duration, deteriorated subjective sleep quality, and worsened daytime sleepiness. Logistic regression analysis demonstrated that the extreme evening type (odds ratio [OR]?=?1.926, p?=?.018) was associated with increased incidence of depressive states and that the extreme morning type (OR?=?0.342, p?=?.038) was associated with the decreased incidence of depressive states, independent of sleep parameters, such as nocturnal awakening (OR?=?1.844, p?<?.001), subjective sleep quality (OR?=?2.471, p?<?.001), and daytime sleepiness (OR?=?1.895, p?=?.001). However, no significant associations were observed between the incidence of depressive states and sleep duration, sleep timing, and sleep debt (levels of insufficient sleep). Although the findings of this study do not demonstrate a causative relationship between evening preference and depression, they do suggest the presence of functional associations between mood adjustment and biological clock systems that regulate diurnal preference. They also suggest that evening preference might increase susceptibility to the induction of mood disorders. (Author correspondence: mishima@ncnp.go.jp)