Polymorphisms In Circadian Genes Research Articles

CLOCK gene 3’UTR and exon 9 polymorphisms show a strong association with essential hypertension in a North Indian population

BackgroundHypertension (HTN) is a medical condition characterized by persistent systolic and diastolic blood pressures of ≥ 140 mmHg and ≥ 90 mmHg, respectively. With more than 1200 million adult patients aged 30–79 years worldwide according to the latest WHO data, HTN is a major health risk factor; more importantly, 46% of patients are unaware of this condition. Essential hypertension (EH), also known as primary hypertension, is the predominant subtype and has a complex etiology that involves both genetic and non-genetic factors. Majority of living organisms are influenced by the light and dark cycle of a day and respond to these changes through an intricate clock referred to as the “biological clock” or “circadian rhythm”. The connection between circadian rhythm and blood pressure is well established, with many studies supporting the role of circadian rhythm gene mutation(s)/polymorphism(s) in EH. To date, no such data are available from any Indian population.MethodsThis case‒control study was conducted on 405 EH patients and 505 healthy controls belonging to the Jammu region of North India after an informed consent was obtained from the participants. A total of three single nucleotide variants, two in the CLOCK gene (rs1801260 and rs34789226) and one in the BMAL1/ARNTL gene (rs6486121), were selected for genotyping. Genotyping was performed via the RFLP technique, and the applicable statistical analyses were performed via the SPSS and SNPStats programs.ResultsLogistic regression analysis revealed a statistically significant association of both CLOCK gene variants rs1801260 (T > C 3’UTR) and rs34789226 (C > T Exon 9) and a nonsignificant association of the BMAL1/ARNTL intronic variant rs6486121 (C > T) with EH. The 3’UTR variant showed a statistically significant association under the codominant (p < 0.0001), dominant (p < 0.0001), and recessive (p = 0.0004) models. In contrast, the exon 9 variant showed a statistically significant negative association under the codominant (p = 0.003) and dominant (p = 0.015) models only. The rs6486121/rs1801260 and rs1801260/rs34789226/rs6486121 haplotypes showed significant differences in their distribution between cases and controls (p < 0.0001). Certain genotypes and haplotypes were found more common in hypertensive males than females.ConclusionThis is a first report linking circadian rhythm gene polymorphisms with EH in any Indian population. The statistically significant association of the CLOCK gene 3’UTR and exon 9 polymorphisms with EH, highlight the potential role of this gene and probably other genes of the circadian pathway in the etiology of EH in the study population. Additionally, our study also revealed that certain genotypes are making males more susceptible to EH.

The correlation of shift work and CLOCK, BMAL1, and PER1 gene polymorphisms with hypertension in healthcare workers: A cross-sectional study

This study aimed to investigate the polymorphisms of circadian clock genes and the association of shift work and gene polymorphisms with hypertension in healthcare workers. This study recruited 222 healthcare workers, of whom 76 had primary hypertension (Hyp group) and 146 served as controls (Control group). General information and working hours were collected through questionnaires. Next, the identification of specific single nucleotide polymorphism (SNP) loci related to the Circadian locomotor output cycles kaput (CLOCK), brain and muscle arnt-like 1 (BMAL1), and PER1 genes was conducted by literature and PDGene database search. Venous blood samples were then collected for DNA extraction, and polymerase chain reaction-restriction fragment length polymorphism techniques were used to analyze the genotyping and allele frequency of the SNP sites. Finally, multivariate logistic regression was employed to analyze the association between various risk factors and hypertension in healthcare workers. Compared to the control group, the Hyp group had significantly higher proportions of alcohol consumption and family history of hypertension, while the average sleep duration and average exercise time were significantly lower. Shift work analysis showed that the Hyp group had a significantly lower average number of evening shifts per month while a much higher average number of night shifts per month compared to the control group. The GG genotype at the CLOCK rs1801260 locus was associated with a lower risk of hypertension (OR = 0.446), and the TT genotype of the BMAL1 rs11022775 locus also showed a similar protective effect (OR = 0.426). However, the genotype distribution of the PER1 rs2735611 locus was not significantly associated with the risk of hypertension. Multivariate regression analysis revealed that a family history of hypertension and insufficient sleep were significantly associated with the risk of hypertension, and the average number of night shifts per month was positively correlated with the risk of hypertension. Specific polymorphisms in the CLOCK and BMAL1 genes may have a protective effect against hypertension in healthcare workers, while polymorphisms in the PER1 gene are not significantly associated with the risk of hypertension. Additionally, a family history of hypertension, insufficient sleep, and shift work patterns may be significant risk factors for hypertension.

Abstract 7320: Expression of circadian rhythm genes and lethal prostate cancer

Abstract Background: The circadian rhythm regulates diverse physiological and oncologic processes. We have previously shown in epidemiology studies that disruption of the circadian rhythm may be associated with increased risk of aggressive prostate cancer, including germline polymorphisms in certain circadian rhythm genes. This study sought to investigate the relationship between tumor circadian rhythm gene expression and lethal prostate cancer. Methods: We studied patients with primary prostate cancer in the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). We created a composite score of mRNA expression using principal components that incorporated 11 circadian rhythm genes: AANAT, ARNTL, CLOCK, CRY1, CSNK1E, MTNR1A, MTNR1B, NPAS2, PER1, PER2, PER3. An age-stratified analysis was performed, and the mean differences of the score both by Gleason score and compared to normal tissue were calculated. The relationship between the score in prostate tumor tissue and lethal prostate cancer (metastases/prostate cancer-specific death) vs. indolent disease (no metastases after &amp;gt;8 years of follow-up) was assessed using logistic regression. The contribution of each gene was evaluated by leave-one-out analysis, generating scores leaving out one gene and assessing the relationship between the modified score and lethal disease. Results: Among 404 cancer patients in HPFS/PHS, there were 119 lethal events over 30 years of follow-up (median: 17 years). The circadian rhythm gene score was lower in tumor tissue compared to tumor-adjacent, histologically normal tissue (mean difference in units of standard deviation [SD] of gene score: -0.31, 95% confidence interval [CI]: -0.48 to -0.15). In addition, the score was lower in Gleason 9-10 compared to Gleason 6 tumors (mean difference in SD units: -1.05, 95% CI: -1.55 to -0.54). The three PER genes were the most strongly correlated with each other and with the score (Spearman correlation coefficients from 0.52-0.88 for the score and 0.31-0.63 between PER genes). Higher circadian rhythm gene scores were inversely associated with lethal prostate cancer (odds ratio [OR] for highest vs. lowest quartile: 0.43, 95% CI: 0.20 to 0.90) in a dose-response fashion and after adjusting for clinical and pathologic factors. The association appeared to be stronger in patients aged ≥65 years (OR for highest vs. lowest quartile: 0.21, 95% CI: 0.08 to 0.47) compared to &amp;lt;65 years at diagnosis (OR: 0.78, 95% CI: 0.29, 2.17). Results were consistent in the leave-one-out analysis for all genes except PER2 (OR for highest vs. lowest quartile: 1.00, 95% CI: 0.55 to 1.83) and PER1 (OR: 0.55, 95% CI: 0.30 to 1). Conclusion: This study examining intratumoral circadian rhythm gene expression contributes further evidence in support of the relationship between circadian rhythm disruption and aggressive prostate cancer. Tumor expression of PER1 and PER2 may be a predominant factor in the association. Citation Format: Jane Bailey Vaselkiv, Sarah C. Markt, Hannah E. Guard, Anqi Wang, Kathryn L. Penney, Konrad H. Stopsack, Lorelei A. Mucci. Expression of circadian rhythm genes and lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7320.

The moderating role of circadian gene polymorphisms in the relationship between sleep disturbance and circulating lymphocyte subsets in colorectal cancer patients

AimWe investigated the impact of sleep disturbance on immune status in colorectal cancer (CRC) patients with consideration of the moderating role of circadian clock gene polymorphisms. MethodsA prospective longitudinal study design was used to collect information regarding sleep disturbance. Blood samples for immunologic assays were obtained the day before the first (baseline) and last cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. Clinical sleep disturbance was compared between the two-time points using the Pittsburgh Sleep Quality Index (PSQI) global score. We analysed single-nucleotide polymorphisms in rs2278749, rs3749474, rs2291738, rs17031614, and rs2287161. The dependent variables included changes in the percentages of CD4+, CD8+, CD19+, and CD16/56+ lymphocytes between the two-time points. The results were analysed using moderated regression analysis; the p-values were adjusted using the false discovery rate. ResultsAmong the 104 patients, no significant dyadic associations were observed between changes in lymphocyte percentages and the PSQI global score. However, the moderated regression analysis revealed five significant associations (rs2287161 with CD8+, rs2278749 and rs2291738 with CD19+, and rs17031614 with CD4+ and CD16/56+ lymphocytes). The inclusion of each interaction resulted in a significant increase (5.7–10.7%) in the variance explained by changes in lymphocyte percentage. ConclusionPatients with specific circadian gene allele types may be more susceptible to immune dysregulation when experiencing sleep disturbances. Considering that sleep disturbance is a modifiable factor that can impact immune regulation, it is essential to prioritise the management of sleep disturbances in CRC patients receiving FOLFOX chemotherapy.

Characteristics of insulin resistance in Korean adults from the perspective of circadian and metabolic sensing genes

BackgroundThe biological clock allows an organism to anticipate periodic environmental changes and adjust its physiology and behavior accordingly.ObjectiveThis retrospective cross-sectional study examined circadian gene polymorphisms and clinical characteristics associated with insulin resistance (IR).MethodsWe analyzed data from 1,404 Korean adults aged 30 to 55 with no history of cancer and cardio-cerebrovascular disease. The population was classified according to sex and homeostasis model assessment of insulin resistance (HOMA-IR) values. Demographics, anthropometric and clinical characteristics, and single nucleotide polymorphisms (SNPs) were analyzed with respect to sex, age, and HOMA-IR values. We used association rule mining to identify sets of SNPs from circadian and metabolic sensing genes that may be associated with IR.ResultsAmong the subjects, 15.0% of 960 women and 24.3% of 444 men had HOMA-IR values above 2. Most of the parameters differed significantly between men and women, as well as between the groups with high and low insulin sensitivity. Body fat mass of the trunk, which was significantly higher in insulin-resistant groups, had a higher correlation with high sensitivity C-reactive protein and hemoglobin levels in women, and alanine aminotransferase and aspartate aminotransferase levels in men. Homozygous minor allele genotype sets of SNPs rs17031578 and rs228669 in the PER3 gene could be more frequently found among women with HOMA-IR values above 2 (p = .014).ConclusionOxidative stress enhanced by adiposity and iron overload, which may also be linked to NRF2 and PER3-related pathways, is related to IR in adulthood. However, due to the small population size in this study, more research is needed.

Unveiling Subtle Geographical Clines: Phenotypic Effects and Dynamics of Circadian Clock Gene Polymorphisms.

Our understanding of the gene regulatory network that constitutes the circadian clock has greatly increased in recent decades, notably due to the use of Drosophila as a model system. In contrast, the analysis of natural genetic variation that enables the robust function of the clock under a broad range of environments has developed more slowly. In the current study, we analyzed comprehensive genome sequencing data from wild European populations of Drosophila, which were densely sampled through time and space. We identified hundreds of single nucleotide polymorphisms (SNPs) in nine genes associated with the clock, 276 of which exhibited a latitudinal cline in their allele frequencies. While the effect sizes of these clinal patterns were small, indicating subtle adaptations driven by natural selection, they provided important insights into the genetic dynamics of circadian rhythms in natural populations. We selected nine SNPs in different genes and assessed their impact on circadian and seasonal phenotypes by reconstructing outbred populations fixed for either of the SNP alleles, from inbred DGRP strains. The circadian free-running period of the locomotor activity rhythm was affected by an SNP in doubletime (dbt) and eyes absent (Eya). The SNPs in Clock (Clk), Shaggy (Sgg), period (per), and timeless (tim) affected the acrophase. The alleles of the SNP in Eya conferred different levels of diapause and the chill coma recovery response.

Relation between single nucleotide polymorphisms in circadian clock relevant genes and cholesterol metabolism

Single nucleotide polymorphisms (SNPs) in circadian clock relevant genes are associated with several metabolic health variables, but little is known about their associations with human cholesterol metabolism. Therefore, this study examined associations between SNPs in ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER2, and PER3 with the intestinal cholesterol absorption markers campesterol and sitosterol, the endogenous cholesterol synthesis marker lathosterol, and total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations in 456 healthy individuals from Western European descent. One SNP in ARNTL2 (rs1037924) showed a significant association with lathosterol. Several SNPs in ARNTL (rs4146388, rs58901760, rs6486121), ARNTL2 (rs73075788), CLOCK (rs13113518, rs35115774, rs6832769), and CRY1 (rs2078074) were significantly associated with intestinal cholesterol absorption. Genetic variants in CRY2, PER2, and PER3 were not significantly associated with intestinal cholesterol absorption or endogenous cholesterol synthesis. None of the SNPs were associated with TC or LDL-C, except for one SNP in PER2 (rs11894491) with serum LDL-C concentrations. The findings suggest that various SNPs in ARNTL, ARNTL2, CLOCK and CRY1 play a role in intestinal cholesterol absorption and endogenous cholesterol synthesis, which was not reflected in TC and LDL-C concentrations. The significant associations between SNPs and intestinal cholesterol absorption and endogenous cholesterol synthesis should be validated in other cohorts.

Single nucleotide polymorphisms (SNPs) in circadian genes: Impact on gene function and phenotype.

Circadian rhythm is an endogenous timing system that allows an organism to anticipate and adapt to daily changes and regulate various physiological variables such as the sleep-wake cycle. This rhythm is governed by a molecular circadian clock mechanism, generated by a transcriptional and translational feedback loop (TTFL) mechanism. In mammals, TTFL is determined by the interaction of four main clock proteins: BMAL1, CLOCK, Cryptochromes (CRY), and Periods (PER). BMAL1 and CLOCK form dimers and initiate the transcription of clock-controlled genes (CCG) by binding an E-box element with the promotor genes. Among CCGs, PERs and CRYs accumulate in the cytosol and translocate into the nucleus, where they interact with the BMAL1/CLOCK dimer and inhibit its activity. Several epidemiological and genetic studies have revealed that circadian rhythm disruption causes various types of disease. In this chapter, we summarize the effect of core clock gene SNPs on circadian rhythm and diseases in humans.

Gene–environment interaction between circadian clock gene polymorphisms and job stress on the risk of sleep disturbances

Sleep disturbances was associated with numerous adverse health outcomes. Many studies have reported that long-term exposure to job stress can lead to sleep disturbances, which may be influenced by genetic and environmental factors. This cross-sectional study investigated whether circadian clock gene polymorphisms modulated the influence of job stress on sleep disturbances in a Chinese Han population, which to our best knowledge has not been explored. The Effort-Reward Imbalance (ERI) scale and the Pittsburgh Sleep Quality Index (PSQI) were both used to access job stress and sleep disturbances. The SNaPshot SNP assay was carried out by screening for circadian clock gene polymorphisms in every participant. Interactions associated with sleep disturbances were assessed by linear hierarchical regression analysis and SPSS macros (PROCESS). Linear hierarchical regression analysis showed that job stress was significantly related to sleep disturbances. Likewise, our study found a significant effect of PER2 rs2304672 polymorphisms on sleep disturbances (p < 0.01), after controlling for confounding factors. In addition, the PER2 rs2304672 genotype modulated the relationship between job stress and sleep disturbances (β = 0.414, p = 0.007). Interestingly, further analysis of the results of the PER2 gene rs2304672 × job stress interaction showed that rs2304672 G-allele carriers had a high-risk effect on sleep disturbances under high job stress. Our results suggest that the PER2 rs2304672 polymorphism may modulate the influence of job stress on sleep disturbances. These findings contribute to the field of sleep disturbances prevention and treatment.

A Predictive Model of Risk Factors for Conversion From Major Depressive Disorder to Bipolar Disorder Based on Clinical Characteristics and Circadian Rhythm Gene Polymorphisms.

BackgroundBipolar disorder (BD) is easy to be misdiagnosed as major depressive disorder (MDD), which may contribute to a delay in treatment and affect prognosis. Circadian rhythm dysfunction is significantly associated with conversion from MDD to BD. So far, there has been no study that has revealed a relationship between circadian rhythm gene polymorphism and MDD-to-BD conversion. Furthermore, the prediction of MDD-to-BD conversion has not been made by integrating multidimensional data. The study combined clinical and genetic factors to establish a predictive model through machine learning (ML) for MDD-to-BD conversion.MethodBy following up for 5 years, 70 patients with MDD and 68 patients with BD were included in this study at last. Single nucleotide polymorphisms (SNPs) of the circadian rhythm genes were selected for detection. The R software was used to operate feature screening and establish a predictive model. The predictive model was established by logistic regression, which was performed by four evaluation methods.ResultsIt was found that age of onset was a risk factor for MDD-to-BD conversion. The younger the age of onset, the higher the risk of BD. Furthermore, suicide attempts and the number of hospitalizations were associated with MDD-to-BD conversion. Eleven circadian rhythm gene polymorphisms were associated with MDD-to-BD conversion by feature screening. These factors were used to establish two models, and 4 evaluation methods proved that the model with clinical characteristics and SNPs had the better predictive ability.ConclusionThe risk factors for MDD-to-BD conversion have been found, and a predictive model has been established, with a specific guiding significance for clinical diagnosis.

Genotyping of ARNTL and CLOCK Circadian Rhythm Gene Polymorphisms in Iranian Patients with Multiple Sclerosis

Background: Multiple sclerosis (MS) is a central nervous system disease accompanied by variable symptoms such as optic neuritis, fatigue, spasticity, neuro-urological dysfunction, paresthesia, and headache. The frequency of MS was reported differently in geographical latitude, which may be in relation to genetic changes in circadian rhythm regulator genes, including aryl hydrocarbon receptor nuclear translocator-like (ARNTL) and circadian locomotor output cycles kaput (CLOCK). Objectives: This study aimed at genotyping rs3789327 in the ARNTL and rs6811520 in the CLOCK genes and their association with MS in the Iranian population. Methods: Totally, 100 patients with relapsing-remitting multiple sclerosis (RRMS) and 100 healthy controls were recruited. DNA extracted from the whole blood of all patients was genotyped by high-resolution melting (HRM) real-time PCR method for the rs3789327 and rs6811520 within the ARNTL and CLOCK genes, respectively, then the HRM results were confirmed by Sanger sequencing method. Results: Our results showed a statistically significant difference in genotype distributions in the CLOCK gene (rs6811520, P = 0.023) in MS and healthy controls, but in the ARNTL gene, there was no significant change in rs3789327 genotypic distribution between MS patients and healthy individuals (P = 0.2). The TC genotype of the rs6811520 was associated with a higher risk for MS [P = 0.006, OR = 4.164, 95% confidence intervals (CI) 1.43 - 12.09]. Conclusions: The present results suggested that genetic variations in the CLOCK gene are a risk factor for MS.

Machine learning and expression analyses reveal circadian clock features predictive of anxiety

Mood disorders, including generalized anxiety disorder, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes. Molecular mechanisms underlying these connections may be direct—via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect—via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3(rs17031614)-AG/CRY1(rs2287161)-CG genotype being the strongest predictor of anxiety risk, particularly in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3 effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

The Association between Circadian Clock Gene Polymorphisms and Metabolic Syndrome: A Systematic Review and Meta-Analysis.

Simple SummaryMetabolic syndrome is a cluster of cardio-metabolic risk factors and comorbidities, including central obesity, hypertension, hyperglycemia, and dyslipidemia. In addition, different studies have shown that the disturbances in circadian rhythm are connected with components of metabolic syndrome. Circadian rhythm is the central regulator of every aspect of human health and metabolism, and metabolic homeostasis is essential in regulating energy metabolism, especially in adipose tissue. Therefore, we aimed to evaluate the association of genetic variations of circadian rhythm genes with metabolic syndrome and its components by a systematic review and meta-analysis. Our findings suggest that some variants of the circadian rhythm gene might be genetic biomarkers applied to predict metabolic syndrome susceptibility.Metabolic syndrome (MetS) is a combination of cardiovascular risk factors associated with type 2 diabetes, obesity, and cardiovascular diseases. The circadian clock gene polymorphisms are very likely to participate in metabolic syndrome genesis and development. However, research findings of the association between circadian rhythm gene polymorphisms and MetS and its comorbidities are not consistent. In this study, a review of the association of circadian clock gene polymorphisms with overall MetS risk was performed. In addition, a meta-analysis was performed to clarify the association between circadian clock gene polymorphisms and MetS susceptibility based on available data. The PubMed and Scopus databases were searched for studies reporting the association between circadian rhythm gene polymorphisms (ARNTL, BMAL1, CLOCK, CRY, PER, NPAS2, REV-ERBα, REV-ERBβ, and RORα) and MetS, and its comorbidities diabetes, obesity, and hypertension. Thirteen independent studies were analyzed with 17,381 subjects in total. The results revealed that the BMAL1 rs7950226 polymorphism was associated with an increased risk of MetS in the overall population. In contrast, the CLOCK rs1801260 and rs6850524 polymorphisms were not associated with MetS. This study suggests that some circadian rhythm gene polymorphisms might be associated with MetS in different populations and potentially used as predictive biomarkers for MetS.

The association of polymorphisms in related circadian rhythm genes and clopidogrel resistance susceptibility.

Previous studies have confirmed that a dynamic change in circadian rhythm will affect platelet activity, resulting in clopidogrel resistance (CR). We attempted to evaluate whether polymorphisms of related circadian rhythm genes are involved in CR in stable coronary artery disease (SCAD) patients. A sum of 204 SCAD patients met our requirements and were recruited, and 96 patients were considered to have CR. After clinical data collection and platelet function evaluation, genomic DNA was isolated from human peripheral blood, and 23 tagSNPs from related circadian rhythm genes were genotyped by GenomeLab SNPstream Genotyping System. After RNA isolation, relative expression of related gene mRNAs (CLOCK, CRY1, CACNA1C and PRKCG) was measured by real-time PCR. The results showed that polymorphisms in CRY1, CACNA1C and PRKCG changed the response to clopidogrel. And then, the rs1801260 polymorphism might lead to higher mRNA expression in CLOCK and potentially induce the occurrence of CR. Additionally, the TC genotype of rs3745406 might lower mRNA expression of PRKCG, resulting in CR. These findings support the hypothesized role of circadian rhythm genes in CR and indicate probable biomarkers for CR susceptibility, providing new insight into individualized medicine for coronary heart disease.

Des gènes circadiens à la sémiologie psychiatrique

Psychiatric disorders, such as bipolar disorder and autism spectrum disorders, are highly inherited. Many studies have reported a higher relative risk of developing these disorders than in general population when there is already an affected individual in the family. The heritability of these disorders varies from 70% to 90%. However, the identification of susceptibility genes to these disorders remains difficult, due to their high clinical and etiological heterogeneity. The combination of endophenotypes and environmental factors in genetic studies shed new lights on the biological pathways that are affected in subjects with psychiatric disorders. In particular, sleep disorders and circadian rhythm abnormalities have been frequently reported in these two disorders. Here, we summarize several associations between sleep disorders or circadian rhythm abnormalities and single nucleotide polymorphisms in circadian genes and in genes encoding enzymes of the melatonin synthesis pathway. In particular, we describe studies reporting that polymorphisms in the circadian genes TIMELESS and RORA may increase the risk of developing bipolar disorder by altering circadian rhythms. In addition, we describe studies showing that genetic variations in acetylserotonin methyltransferase (ASMT) identified in patients with psychiatric disorders affect its enzymatic activity. This approach may have therapeutic benefits in bipolar disorders, through the assessment of sleep and circadian rhythms, and a personal management of these alterations.

Circadian Clock Gene Polymorphisms and Sleep-Onset Problems in a Population-Based Cohort Study: The Yamagata Study.

A number of genome-wide association studies have investigated sleep phenotypes and disorders in humans. However, the contribution of genetic variation to sleep problems in Japanese populations has remained unclear. Sleep-onset problems are the most common symptom of insomnia. Here, we examined the relationship between single nucleotide polymorphisms (SNPs) of BMAL1 (ARNTL1), CLOCK, CRY1, CRY2, and PER2, which are genes involved in the clock mechanism, and sleep-onset problems in a Japanese general population. This study included 1,397 subjects aged ≥ 40 years who participated in an annual health check-up in Yamagata Prefecture. A total of 80 SNPs of 5 circadian clock genes were analyzed. Multivariate logistic regression analyses identified variant rs11113179 in CRY1 and variants rs1026071 and rs1562438 in BMAL1 as genetic risk factors for sleep induction disorder. These findings suggest that CRY1 and BMAL1 polymorphisms are related to sleep-onset problems in a Japanese general population. However, none of the SNPs remained significant at a stringent level of multiple correction.

Variants in Circadian Rhythm Gene Cry1 Interacts with Healthy Dietary Pattern for Serum Leptin Levels: a Cross-sectional Study.

Circadian disruption causes obesity and other metabolic disorders. There is no research considering the role of Cryptochromes (Cry) 1 body clock gene and major dietary patterns on serum leptin level and obesity. We aimed to investigate the interaction between Cry1 circadian gene polymorphisms and major dietary patterns on leptin and obesity related measurements. This study was performed on 377 overweight and obese women. Mean age and body mass index (BMI) of study subjects were 36.64 ± 9.02 years and 30.81 ± 3.8 kg/m2, respectively. Dietary assessment was done using a validated 147-item food frequency questionnaire. Cry1 rs2287161 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Generalized linear models were used for interaction analysis. Healthy and unhealthy dietary pattern (HDP and UDP, respectively) were extracted using factor analysis (principal component analysis). Our study revealed a significant higher weight (p = 0.003) and BMI (p = 0.042) in women carrying CC homozygote compared with G allele carriers. Moreover, our findings showed a significant gene-diet interaction between HDP and Cry1 rs2287161 on BMI (p = 0.034) and serum leptin level (p = 0.056) in which, BMI and serum leptin level were lower in subjects with CC genotype than in those with GG genotype while following HDP. This study suggests a significant interaction between Cry1 rs2287161 polymorphisms and HDP on BMI and serum leptin and the lowering effects were apparent among C allele carriers compared to G allele ones. This data highlights the role of dietary pattern in relation of gene and obesity.

Association of the Serotonin 2A Receptor rs6311 Polymorphism with Diurnal Preference in Koreans.

Objective Evidence for the association between circadian rhythm delay and depression is accumulating. Genetic studies have shown that certain polymorphisms in circadian genes are potential genetic markers of diurnal preference. Along with circadian genes, there is a growing interest in other genetic effects on circadian rhythms. This study evaluated whether the HTR2A rs6311 (-1438C/T) polymorphism is associated with diurnal preference in a Korean population. Methods A total of 510 healthy subjects were included in this study. All subjects were genotyped for the HTR2A rs6311 polymorphism and they completed the Korean version of the composite scale of morningness (CSM). Results The C allele carriers (C/C+C/T) showed significantly higher CSM scores compared to C allele non-carriers (T/T) (t=2.22, p=0.03), suggesting the existence of a morning chronotype tendency in C allele carriers. In other words, the T/T genotype may be associated with the evening chronotype. Conclusion These results suggest that the HTR2A rs6311 polymorphism may be associated with diurnal preference in a healthy Korean population. The absence of the C allele may be responsible for the increasing susceptibility to eveningness in the Korean population. Further studies on HTR2A polymorphisms that evaluate their interactions with various candidate genes and differences in phenotypic expression of polymorphisms according to ethnic groups are warranted to fully understand their association with diurnal preference.

Association analysis between chronic obstructive pulmonary disease and polymorphisms in circadian genes.

BackgroundCircadian genes have been suggested to play an important role in lung pathology. However, it remains unknown whether polymorphisms of these genes are associated with chronic obstructive pulmonary disease (COPD). Here, we aimed to investigate the association of circadian genes polymorphisms with COPD in a case-control study of 477 COPD patient and 323 control Han Chinese persons.MethodsGenotyping assays were carried out for nine single nucleotide polymorphisms (SNPs) from five circadian genes (PER3, CLOCK, RORB, BMAL1 and CRY2) that were previously identified in lung pathology. Age, sex, BMI and smoking status and comorbidities were recorded for all subjects.ResultsNo significant association was found in all SNP sites in overall subjects and no significant difference was found in age, sex, smoking status stratification analysis.DiscussionThe findings of this investigation indicated the effect of circadian genes polymorphisms on COPD susceptibility may only be small and possibly dependent on the subject factors, such as age and sex.

Depression and anxiety symptoms correlate with diurnal preference, sleep habits, and Per3 VNTR polymorphism (rs57875989) in a non-clinical sample

BackgroundEvidences suggest that alterations in circadian rhythms trigger the development of mental disorders. Eveningness, sleep behavior, and circadian genes polymorphisms have been associated with depression and anxiety symptomatology. However, the mechanism underlying these interactions is not well understood. We investigated the contribution of diurnal preference, sleep habits, and PER3 VNTR polymorphism (rs57875989) to depression and anxiety symptoms in a Northeast sample from the Brazilian population. MethodsEight hundred and four young adults completed the Morningness-Eveningness (MEQ), Munich Chronotype (MCTQ), Center for Epidemiologic Studies – Depression (CES-D), and Beck Anxiety Inventory (BAI) questionnaires. All participants were genotyped and linear regression was performed to test the interactions between the genetic /behavioral variants and depression/ anxiety symptoms. ResultsEveningness and sleep behaviors (bedtime, wake-up time, sleep duration, and midpoint of sleep) were correlated with depression symptomatology, specifically in somatic factors of the CES-D questionnaire. No correlation was found between diurnal preference/sleep habits with anxiety symptoms for both BAI total score and its factors. However, women with PER34/4 genotype showed less interpesonal affect in depression symptomatology and more anxiety symptoms in four factors of the BAI questionnaire. LimitationsMainly because this study was based on self-report questionnaires and was limited to undergraduate students aging 18 to 30 years old. ConclusionThese results reinforce a role for sleep and diurnal preference in depression, and PER3 VNTR polymorphism in anxiety symptomatology, particularly in women.