The Opioid Receptor Mu 1 (OPRM1) rs1799971 and Catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia

This is the accepted manuscript version of the following article: Aslaksen, P.M., Forsberg, J.T. & Gjerstad, J. (2018). The Opioid Receptor Mu 1 (OPRM1) rs1799971 and Catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia. Pain. https://doi.org/10.1097/j.pain.0000000000001370. Published version available at https://doi.org/10.1097/j.pain.0000000000001370.The placebo effect is considered the core example of mind-body interactions. However, individual differences produce large placebo response variability in both healthy volunteers and patients. The placebo response in pain, placebo analgesia, may be dependent on both the opioid system and the dopaminergic system. Previous studies suggest that genetic variability affects the function of these 2 systems. The aim of this study was therefore to address the interaction between the single nucleotide polymorphisms opioid receptor mu 1 (OPRM1) rs1799971 and catechol-O-methyltransferase (COMT) rs4680 on placebo analgesia. Two hundred ninety-six healthy volunteers participated in a repeated-measures experimental design where thermal heat pain stimuli were used as pain stimuli. Participants were randomized either to a placebo group receiving placebo cream together with information that the cream would reduce pain, or to a natural history group receiving the same pain stimuli as the placebo group without any application of cream or manipulation of expectation of pain levels. The results showed that the interaction between OPRM1 rs1799971 and COMT rs4680 was significantly associated with the placebo analgesic response. Participants with OPRM1 Asn/Asn combined with COMT Met/Met and Val/Met reported significant pain relief after placebo administration, whereas those with other combinations of the OPRM1 and COMT genotypes displayed no significant placebo effect. Neither OPRM1 nor COMT had any significant influence on affective changes after placebo administration. As shown in this study, genotyping with regard to OPRM1 and COMT may predict who will respond favorably to placebo analgesic treatment

Dispositional affect as a moderator in the relationship between role conflict and exposure to bullying behaviors

Stressors in the work environment and individual dispositions among targets have been established separately as antecedents and risk factors of workplace bullying. However, few studies have examined these stressors in conjunction in order to determine personal dispositions among targets as possible moderators in the work stressor–bullying relationship. The aim of the present study was to examine multiple types of dispositional affect among targets as potential moderators in the relationship between role conflict and exposure to bullying behaviors, employing two independent cross-sectional samples. The first sample comprised 462 employees from a Norwegian sea transport organization, where trait anger and trait anxiety were included moderators. The second sample was a nationwide probability sample of the Norwegian working population and comprised 1,608 employees randomly drawn from The Norwegian Central Employee Register, where positive and negative affect were included moderators. The results showed that trait anger, trait anxiety, and negative affect strengthened the positive relationship between role conflict and reports of bullying behaviors. Positive affect did not moderate this relationship. We conclude that the association between role conflict and bullying is particularly strong for those scoring high on trait anger, trait anxiety, and negative affect.publishedVersio

The 5-HTTLPR rs25531 LALA-genotype increases the risk of insomnia symptoms among shift workers

Background Previous studies indicate that shift work tolerance may be associated with individual factors including genetic variability in the gene encoding the serotonin transporter 5-HTT (SLC6A4). The present study aimed to explore the interaction between work schedule (shift work versus non-shift work), genetic variability in SLC6A4 and insomnia symptoms. Methods The study was based on a national probability sample survey of 987 Norwegian employees drawn from The Norwegian Central Employee Register by Statistics Norway. Insomnia symptoms were assessed by three items reflecting problems with sleep onset, sleep maintenance, and early morning awakenings. Genotyping concerning SLC6A4 (the 5-HTTLPR S versus L and the SNP rs25531 A versus G) was carried out using a combination of gel-electrophoresis and TaqMan assay. Results Using the LALA genotype as a reference a main effect of the SS genotype (B = 0.179; 95% CI = 0.027–0.330) was found. In addition, a main effect of work schedule (0 = non shift, 1 = shift work) was found (B = 0.504; 95% CI = 0.185–0.823). The genotype x work schedule interaction was significant for all genotypes; SLA (B = −0.590; 95% CI = −0.954–0.216), LALG (B = −0.879; 95% CI = −1.342–0.415), SLG (B = −0.705; 95% CI = −1.293–0.117) and SS (B = −0.773; 95% CI = −1.177–0.369) indicating higher insomnia symptom scores among LALA-participants compared to participants with other genotypes when working shifts. Conclusions The ability to cope with shift work is associated with the combination of the SLC6A4 variants 5-HTTLPR and SNP rs25531. Our findings demonstrated that the LALA-genotype increases the risk of insomnia symptoms among shift workers.acceptedVersio

Dispositional Affect as a Moderator in the Relationship Between Role Conflict and Exposure to Bullying Behaviors

Stressors in the work environment and individual dispositions among targets have been established separately as antecedents and risk factors of workplace bullying. However, few studies have examined these stressors in conjunction in order to determine personal dispositions among targets as possible moderators in the work stressor–bullying relationship. The aim of the present study was to examine multiple types of dispositional affect among targets as potential moderators in the relationship between role conflict and exposure to bullying behaviors, employing two independent cross-sectional samples. The first sample comprised 462 employees from a Norwegian sea transport organization, where trait anger and trait anxiety were included moderators. The second sample was a nationwide probability sample of the Norwegian working population and comprised 1,608 employees randomly drawn from The Norwegian Central Employee Register, where positive and negative affect were included moderators. The results showed that trait anger, trait anxiety, and negative affect strengthened the positive relationship between role conflict and reports of bullying behaviors. Positive affect did not moderate this relationship. We conclude that the association between role conflict and bullying is particularly strong for those scoring high on trait anger, trait anxiety, and negative affect

Exposure to workplace bullying, distress, and insomnia. The moderating role of the miR-146a genotype

Several lines of evidence show that systematic exposure to negative social acts at the workplace i.e., workplace bullying, results in symptoms of depression and anxiety among those targeted. However, little is known about the association between bullying, inflammatory genes and sleep problems. In the present study, we examined the indirect association between exposure to negative social acts and sleep through distress, as moderated by the miR-146a genotype. The study was based on a nationally representative survey of 1179 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to workplace bullying was measured with the 9-item version of Negative Acts Questionnaire – Revised (NAQ-R) inventory. Seventeen items from Hopkins Symptom Checklist (HSCL-25) was used to measure distress. Insomnia was assessed with three items reflecting problems with sleep onset, maintenance of sleep and early morning awakening. Genotyping with regard to miR146a rs2910164, previously linked to inflammatory processes, was carried out using Taqman assay. The data revealed that individuals systematically exposed to negative social acts at the workplace reported higher levels of sleep problems than non-exposed individuals. Moreover, the relationship between distress induced by exposure to negative social acts and insomnia was significantly stronger for individuals with the miR-146a GG genotype. Thus, the miR-146a genotype moderated the association between distress and insomnia among individuals exposed to negative social acts. The present report support the hypothesis that inflammation could play a role in stress-induced insomnia among individuals exposed to workplace bullying.publishedVersio

The role of leadership practices in the relationship between role stressors and exposure to bullying behaviours – a longitudinal moderated mediation design

Role conflicts and role ambiguity have been identified as important risk factors for exposure to workplace bullying, particularly when combined with inadequate leadership practices. Even though role ambiguity theoretically can be considered a causal precursor to role conflicts, previous research has mainly examined these role stressors as concurrent predictors of workplace bullying. The present study provides a more nuanced analysis by investigating role conflicts as a mediator in the relationship between role ambiguity and exposure to bullying behaviours. Adding to the understanding of the bullying process we also considered the possible moderating roles of laissez-faire and transformational leadership in the role stressor–bullying relationship. Employing a national probability sample of 1,164 Norwegian workers, with three measurements across a 12-month period, the results showed an indirect effect of employees’ role ambiguity on subsequent exposure to bullying behaviours through employees’ experience of role conflicts. Moreover, laissez-faire leadership exacerbated, while transformational leadership attenuated, the indirect relationship between role ambiguity and exposure to bullying behaviours through role conflicts. In summary, the present data shows that when the management of organisations neglects its inherent responsibility to adequately address employees’ experiences of role ambiguity and role conflicts, the risk of exposure to workplace bullying is likely to increase.publishedVersio

Exposure to Workplace Bullying, Distress, and Insomnia: The Moderating Role of the miR-146a Genotype

Several lines of evidence show that systematic exposure to negative social acts at the workplace i.e., workplace bullying, results in symptoms of depression and anxiety among those targeted. However, little is known about the association between bullying, inflammatory genes and sleep problems. In the present study, we examined the indirect association between exposure to negative social acts and sleep through distress, as moderated by the miR-146a genotype. The study was based on a nationally representative survey of 1179 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. Exposure to workplace bullying was measured with the 9-item version of Negative Acts Questionnaire – Revised (NAQ-R) inventory. Seventeen items from Hopkins Symptom Checklist (HSCL-25) was used to measure distress. Insomnia was assessed with three items reflecting problems with sleep onset, maintenance of sleep and early morning awakening. Genotyping with regard to miR-146a rs2910164, previously linked to inflammatory processes, was carried out using Taqman assay. The data revealed that individuals systematically exposed to negative social acts at the workplace reported higher levels of sleep problems than non-exposed individuals. Moreover, the relationship between distress induced by exposure to negative social acts and insomnia was significantly stronger for individuals with the miR-146a GG genotype. Thus, the miR-146a genotype moderated the association between distress and insomnia among individuals exposed to negative social acts. The present report support the hypothesis that inflammation could play a role in stress-induced insomnia among individuals exposed to workplace bullying

Preventing and Neutralizing the Escalation of Workplace Bullying. The Role of Conflict Management Climate

Workplace bullying is, by definition, a gradually escalating process, theorized to occur from psychosocial stressors when there is a lack of management intervention in escalating conflicts, and a lack of fair and robust conflict management procedures in the organization. Based on national probability survey data gathered in 2015–2016 from the official Norwegian employee-register, we investigated how a strong perceived climate for conflict management may buffer the escalation of workplace bullying over time. A total of 1197 respondents participated in the study at two measuring points. The average age at baseline was 45.20 years (SD = 9.98), and the sample consisted of 52.1% women and 47.9% men. Structural equation modelling in Mplus 7.4 was used to test the construct validity and the study’s hypothesis. As expected, the analyses showed that a strong conflict management climate buffered the escalation of workplace bullying. Exposure to bullying behaviour at T1 largely explained (47%) new and increased instances of bullying behaviour at T2, but only for those employees working in what they perceived as a weak conflict management climate. We conclude that a strong conflict management climate neutralizes the escalation and development of workplace bullying.publishedVersio

Exposure to workplace bullying, microRNAs and pain. Evidence of a moderating effect of miR-30c rs928508 and miR-223 rs3848900

Prolonged exposure to bullying behaviors may give rise to symptoms such as anxiety, depression and chronic pain. Earlier data suggest that these symptoms often are associated with stress-induced low-grade systemic inflammation. Here, using data from both animals and humans, we examined the moderating role of microRNAs (miRNAs, miRs) in this process. In the present study, a resident-intruder paradigm, blood samples, tissue harvesting and subsequent qPCR analyses were used to screen for stress-induced changes in circulating miRNAs in rats. The negative acts questionnaire (NAQ), TaqMan assays and a numeric rating scale (NRS) for pain intensity were then used to examine the associations among bullying behaviors, relevant miRNA polymorphisms and pain in a probability sample of 996 Norwegian employees. In rats, inhibited weight gain, reduced pituitary POMC expression, adrenal Nr3c1 mRNA downregulation, as well as increased miR-146a, miR-30c and miR-223 in plasma were observed following 1 week of repeated exposure to social stress. When following up the miRNA findings from the animal study in the human working population, a stronger relationship between NAQ and NRS scores was observed in subjects with the miR-30c GG genotype (rs928508) compared to other subjects. A stronger relationship between NAQ and NRS scores was also seen in men with the miR-223 G genotype (rs3848900) as compared to other men. Our findings show that social stress may induce many physiological changes including changed expression of miRNAs. We conclude that the miR-30c GG genotype in men and women, and the miR-223 G genotype in men, amplify the association between exposure to bullying behaviors and pain.publishedVersio

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2,500 fewer steps compared to placebo (pinteraction=0.04). There were no differences between clonidine and placebo amongst patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (pint=0.003) and quality of life (pint=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions