Perceived stress is related to lower blood pressure in a Swedish cohort.

AIMS: General psychosocial stress and job strain have been related to blood pressure (BP) with conflicting results. This study sought to explore the contribution of several lifestyle factors in the relation between general psychosocial stress, job strain and BP. METHODS: This cross-sectional study investigated the association of general stress and job strain with systolic BP (SBP) and diastolic BP in a sample of 9441 employed individuals from the EpiHealth cohort. General stress was measured by the Perceived Stress Scale. Job strain was assessed with the Job Content Questionnaire, assessing two dimensions of job strain: psychological job demand and decision latitude. Linear regression and sensitivity analysis were performed. RESULTS: At the uncorrected model, general stress, job demand and decision latitude were all inversely associated with SBP. After further adjustment for lifestyle and health parameters, only general stress was associated with SPB (ß coefficient: -0.103; 95% confidence interval -0.182 to 0.023). CONCLUSIONS: General stress is associated with lower SBP independently of lifestyle in middle-aged adults. Our findings point towards a major contribution for job-unrelated stressors in determining SBP and support the pivotal role of lifestyle behaviours and health status in modulating the effect of stress on BP, calling for a careful selection of confounders.

Differential DNA Methylation of the Genes for Amyloid Precursor Protein, Tau, and Neurofilaments in Human Traumatic Brain Injury.

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM), and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH, and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.

Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia.

IMPORTANCE: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. AIMS: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. METHODS: A cross-sectional cohort study based on baseline data collected between 2006-2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. RESULTS: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10-4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01-1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). CONCLUSION: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.

Personality, lifestyle and job satisfaction: causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort.

Job-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536). Both single variable and multivariable MR analyses were used to determine the effect of each trait on job satisfaction. We observed a clear evidence of a causal association between neuroticism and job satisfaction. In single variable MR, one standard deviation (1 SD) higher genetically determined neuroticism score (4.07 units) was associated with -0.31 units lower job satisfaction (95% confidence interval (CI): -0.38 to -0.24; P = 9.5 × 10-20). The causal associations remained significant after performing sensitivity analyses by excluding invalid genetic variants from GRSNeuroticism (ß(95%CI): -0.28(-0.35 to -0.21); P = 3.4 x 10-15). Education (0.02; -0.08 to 0.12; 0.67) and physical activity (0.08; -0.34 to 0.50; 0.70) did not show any evidence for causal association with job satisfaction. When genetic instruments for neuroticism, education and physical activity were included together, the association of neuroticism score with job satisfaction was reduced by only -0.01 units, suggesting an independent inverse causal association between neuroticism score (P = 2.7 x 10-17) and job satisfaction. Our findings show an independent causal association between neuroticism score and job satisfaction. Physically active lifestyle may help to increase job satisfaction despite presence of high neuroticism scores. Our study highlights the importance of considering the confounding effect of negative personality traits for studies on job satisfaction.

Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.

Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification 'Compulsive Sexual Behavior Disorder' is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD - cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.

Significantly altered peripheral blood cell DNA methylation profile as a result of immediate effect of metformin use in healthy individuals.

BACKGROUND: Metformin is a widely prescribed antihyperglycemic agent that has been also associated with multiple therapeutic effects in various diseases, including several types of malignancies. There is growing evidence regarding the contribution of the epigenetic mechanisms in reaching metformin's therapeutic goals; however, the effect of metformin on human cells in vivo is not comprehensively studied. The aim of our study was to examine metformin-induced alterations of DNA methylation profiles in white blood cells of healthy volunteers, employing a longitudinal study design. RESULTS: Twelve healthy metformin-naïve individuals where enrolled in the study. Genome-wide DNA methylation pattern was estimated at baseline, 10 h and 7 days after the start of metformin administration. The whole-genome DNA methylation analysis in total revealed 125 differentially methylated CpGs, of which 11 CpGs and their associated genes with the most consistent changes in the DNA methylation profile were selected: POFUT2, CAMKK1, EML3, KIAA1614, UPF1, MUC4, LOC727982, SIX3, ADAM8, SNORD12B, VPS8, and several differentially methylated regions as novel potential epigenetic targets of metformin. The main functions of the majority of top-ranked differentially methylated loci and their representative cell signaling pathways were linked to the well-known metformin therapy targets: regulatory processes of energy homeostasis, inflammatory responses, tumorigenesis, and neurodegenerative diseases. CONCLUSIONS: Here we demonstrate for the first time the immediate effect of short-term metformin administration at therapeutic doses on epigenetic regulation in human white blood cells. These findings suggest the DNA methylation process as one of the mechanisms involved in the action of metformin, thereby revealing novel targets and directions of the molecular mechanisms underlying the various beneficial effects of metformin. TRIAL REGISTRATION: EU Clinical Trials Register, 2016-001092-74. Registered 23 March 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001092-74/LV .

A MIR4646 associated methylation locus is hypomethylated in adolescent depression.

BACKGROUND: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. METHODS: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n=93) and validation data set 1 (n=78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n=58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. RESULTS: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p<10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p<0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p<0.05). LIMITATIONS: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. CONCLUSION: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.