Common Genetic Variation Near Melatonin Receptor 1A Gene Linked to Job-Related Exhaustion in Shift Workers.

Study Objectives: Tolerance to shift work varies; only some shift workers suffer from disturbed sleep, fatigue, and job-related exhaustion. Our aim was to explore molecular genetic risk factors for intolerance to shift work. Methods: We assessed intolerance to shift work with job-related exhaustion symptoms in shift workers using the emotional exhaustion subscale of the Maslach Burnout Inventory-General Survey, and carried out a genome-wide association study (GWAS) using Illumina's Human610-Quad BeadChip (n = 176). The most significant findings were further studied in three groups of Finnish shift workers (n = 577). We assessed methylation in blood cells with the Illumina HumanMethylation450K BeadChip, and examined gene expression levels in the publicly available eGWAS Mayo data. Results: The second strongest signal identified in the GWAS (p = 2.3 × 10E-6) was replicated in two of the replication studies with p < .05 (p = 2.0 × 10E-4 when combining the replication studies) and indicated an association of job-related exhaustion in shift workers with rs12506228, located downstream of the melatonin receptor 1A gene (MTNR1A). The risk allele was also associated with reduced in silico gene expression levels of MTNR1A in brain tissue and suggestively associated with changes in DNA methylation in the 5' regulatory region of MTNR1A. Conclusions: These findings suggest that a variant near MTNR1A may be associated with job-related exhaustion in shift workers. The risk variant may exert its effect via epigenetic mechanisms, potentially leading to reduced melatonin signaling in the brain. These results could indicate a link between melatonin signaling, a key circadian regulatory mechanism, and tolerance to shift work.

GENETIC CHARACTERIZATION OF H13 AND H16 INFLUENZA A VIRUSES IN GULLS (LARUS SPP.) WITH CLINICALLY SEVERE DISEASE AND CONCURRENT CIRCOVIRUS INFECTION.

Influenza A viruses (IAVs) of the subtypes H13 and H16 are primarily found in gulls ( Larus spp., order Charadriiformes). Although the gull-adapted subtypes replicate efficiently during infection, gulls usually remain apparently healthy during infection. Avian influenza virus isolates are generally separated into two distinct populations, North American and Eurasian, because of the limited gene flow between the continents. Reassortment between these lineages does occur occasionally; however, direct intercontinental transmission of all eight gene segments is rare. Extensive research has been done to understand the ecology of IAV subtypes that naturally circulate in ducks (order Anseriformes), but the ecology of H13 and H16 IAVs in gulls remains far less studied. In Finland, gulls were screened for IAVs for passive (dead and diseased gulls) and active (clinically healthy gulls) surveillance purposes during the years 2005-10. During that period, 11 H13, two H16 viruses, and one H3N8 IAV were detected. We sequenced partial and full-length hemagglutinin genes of these gull-origin IAVs for phylogenetic assessments. All but one of the H13 genes clustered together with northern European and northeastern Asian viruses, whereas one virus clustered with North American viruses. Interestingly, a high rate (10/14) of these low-pathogenic IAVs was detected in dead or diseased gulls. The atypical clinical status of the IAV-positive gulls and previous observations of circovirus-like inclusion bodies in diseased gulls during autopsies, led us to screen for concurrent circovirus infections in our samples. The DNA of circovirus, an immunosuppressive pathogen of both birds and mammals, was detected in 54% (7/13) of the tested IAV-positive gulls, whereas only 25% (14/56) of our panel of IAV-negative gulls tested positive by circovirus PCR.

Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort.

BACKGROUND: Shift-working nurses are exposed to a stressful work environment, which puts them at an increased risk for burnout and depression. We explored the effect of environmental stress on serotonin transporter gene (SLC6A4) promoter methylation among nurses from high and low work stress environments. METHODOLOGY: Using bisulfite sequencing, we investigated the methylation status of five CpG residues of a CpG-rich region in the promoter of SLC6A4 by comparing female shift working nurses from a high work stress environment (n = 24) to low work stress environment (n = 25). We also analyzed the association of 5-HTTLPR polymorphism at 5' end of SLC6A4. Work stress was assessed by the Karasek's Model and possible signs of burnout or depression were measured by the Maslach Burnout Index General Survey and Beck Depression Index. Methylation levels were assessed by bisulfite sequencing of DNA extracted from peripheral blood leucocytes. Restriction enzyme treatment followed by standard PCR was used to identify 5-HTTLPR genotypes. PRINCIPAL FINDINGS: We found that nurses in the high stress environment had significantly lower promoter methylation levels at all five CpG residues compared to nurses in the low stress environment (p<0.01). There was no significant interaction of 5-HTTLPR genotype and work stress with methylation (p = 0.58). In unadjusted (bivariate) analysis, burnout was not significantly associated to methylation levels. However, when mutually adjusted for both, burnout and work stress were significant contributors (p = 0.038 and p<0.0001 respectively) to methylation levels. CONCLUSIONS: Our findings show that environmental stress is concurrent with decreased methylation of the SLC6A4 promoter. This may lead to increased transcriptional activity of the gene, increased reuptake of serotonin from synaptic clefts, and termination of the activity of serotonin. This could present a possible coping mechanism for environmental stress in humans that could eventually increase risk for disturbed functional capability and experience of depressed mood in long-term stress.

Molecular epidemiology of outbreak-associated and wild-waterfowl-derived newcastle disease virus strains in Finland, including a novel class I genotype.

Newcastle disease (ND) is a highly contagious, severe disease of poultry caused by pathogenic strains of Newcastle disease virus (NDV; or avian paramyxovirus-1). NDV is endemic in wild birds worldwide and one of the economically most important poultry pathogens. Most of the published strains are outbreak-associated strains, while the apathogenic NDV strains that occur in wild birds, posing a constant threat to poultry with their capability to convert into more virulent forms, have remained less studied. We screened for NDV RNA in cloacal and oropharyngeal samples from wild waterfowl in Finland during the years 2006 to 2010: 39 of 715 birds were positive (prevalence, 5.5%). The partial or full-length F genes of 37 strains were sequenced for phylogenetic purposes. We also characterized viruses derived from three NDV outbreaks in Finland and discuss the relationships between these outbreak-associated and the wild-bird-associated strains. We found that all waterfowl NDV isolates were lentogenic strains of class I or class II genotype I. We also isolated a genetically distinct class I strain (teal/Finland/13111/2008) grouping phylogenetically together with only strain HIECK87191, isolated in Northern Ireland in 1987. Together they seem to form a novel class I genotype genetically differing from other known NDVs by at least 12%.

Mat1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipocyte differentiation.

Mammalian Cdk7, cyclin H, and Mat1 form the kinase submodule of transcription factor IIH (TFIIH) and have been considered ubiquitously expressed elements of the transcriptional machinery. Here we found that Mat1 and Cdk7 levels are undetectable in adipose tissues in vivo and downregulated during adipogenesis, where activation of peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a critical differentiation switch. Using both Mat1(-/-) mouse embryonic fibroblasts and Cdk7 knockdown approaches, we show that the Cdk7 complex is an inhibitor of adipogenesis and is required for inactivation of PPARgamma through the phosphorylation of PPARgamma-S112. The results demonstrate that the Cdk7 submodule of TFIIH acts as a physiological roadblock to adipogenesis by inhibiting PPARgamma activity. The observation that components of TFIIH are absent from transcriptionally active adipose tissue prompts a reevaluation of the ubiquitous nature of basal transcription factors in mammalian tissues.