Search

Fatigue is a prevalent symptom associated with decreased quality of life and increased mortality in individuals with end stage renal disease (ESRD), yet causes of fatigue in individuals with ESRD remain poorly understood. We examined gene expression of Neuronal PAS Domain Protein 2 (NPAS2) in relation to patient-reported fatigue in 122 individuals with ESRD. Independent samples t-tests were used to examine NPAS2 gene expression profiles of: non-fatigue versus fatigue. Multivariable regression analyses were used to examine the relationship between fatigue and numerous variables including depression. Participants were approximately 58 years old (+/- 13.2 years), 78% African American ( n = 95), and 72% male ( n = 88). The phenotype of fatigue was not significantly associated with gene expression of NPAS2 but was significantly associated with depression ( p < .001). This study suggests that further research should examine the causal mechanism between depression and fatigue in order to identify genetic factors that could explain the high comorbidity of depression and fatigue.

Background: Emotional health disturbances are common after aneurysmal subarachnoid hemorrhage (aSAH) and their causes are largely unexplored. Corticotropin-releasing hormone receptor 1 (CRHR1) is a key factor in stress reactivity and development of mental health disturbances after adverse life-events., Methods: We explore the effect of CRHR1 genotype on mental health after aSAH in a retrospective cohort study. One hundred twenty-five patients have been assessed using EST-Q mental health questionnaire. Genotyping of CRHR1 single nucleotide polymorphisms (SNP-s) was performed (Rs7209436, Rs110402, Rs242924)., Results: Fatigue was present in almost half of aSAH patients, depression and anxiety in one-third. There was a high prevalence of insomnia and panic complaints. Rs110402 minor allele decreased the risk of depression (OR = 0.25, p = 0.027 for homozygotes). Depression was present in 14% vs 41% in minor and major allele homozygotes, respectively. Rs110402, Rs242924 and Rs7209436 minor alleles and TAT-haplotype, formed by them, were protective against fatigue. After Bonferroni correction only the association of Rs110402 with fatigue remained statistically significant (OR = 0.21, p = 0.006 for minor allele homozygotes). Results remained statistically significant when adjusted for gender, admission state, age and time from aSAH. In multiple regression analysis occurrence of fatigue was dependent on anxiety, modified Rankin score and Rs110402 genotype (R 2  = 0.34, p <  0.001)., Conclusions: CRHR1 minor genotype was associated with a lower risk of fatigue and depression after aSAH. Genetic predisposition to mental health disturbances associated with negative life-events could be a risk factor for fatigue and depression after aSAH and selected patients might benefit from advanced counselling in the recovery phase.

The 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with high phenotypic variability, including somatic disorders like congenital heart disease and psychiatric disorders such as schizophrenia, anxiety disorders, and mood disorders. Clinical observations suggest that many patients with 22q11.2DS suffer from severe fatigue. However, to the best of our knowledge, no previous study has investigated the potential association between 22q11.2DS and fatigue. Twenty-nine patients (mean age 26.8, 18-38 y) with 22q11.2DS completed the multidimensional fatigue inventory (MFI) measuring severity of fatigue. The results of the study group were compared with published population norms. In addition, cross-sectional associations between fatigue, depression (Beck Depression Inventory-BDI), and a quality of life questionnaire (WHO) in patients with 22q11.2 DS were examined. Subscales and total MFI scores were significantly higher in adults with 22q11.2DS. Approximately 80% of the study group had a total MFI score above the mean of the norms. A significant correlation between depressive symptoms and fatigue was found. Fatigue was also significantly associated with quality of life scores, specifically the general score, psychological health, and environment. This is the first report of high levels of fatigue in adults with the 22q11.2DS. Fatigue is a frequent complaint in this age group and should get the necessary attention given its association with quality of life and depression severity. Taking into account the multisystem nature of the 22q11.2DS, we recommend a systematic clinical examination to exclude underlying somatic or psychiatric causes of fatigue. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Patients with Cushing's Syndrome (CS) in remission were used as a model to test the hypothesis that long-standing excessive cortisol exposure induces changes in DNA methylation that are associated with persisting neuropsychological consequences. Genome-wide DNA methylation was assessed in 48 women with CS in long-term remission (cases) and 16 controls matched for age, gender and education. The Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue, depression and anxiety. Cases had lower average global DNA methylation than controls (81.2% vs 82.7%; p = 0.002). Four hundred and sixty-one differentially methylated regions, containing 3,246 probes mapping to 337 genes were identified. After adjustment for age and smoking, 731 probes in 236 genes were associated with psychopathology (fatigue, depression and/or anxiety). Twenty-four gene ontology terms were associated with psychopathology; terms related to retinoic acid receptor signalling were the most common (adjusted p = 0.0007). One gene in particular, COL11A2, was associated with fatigue following a false discovery rate correction. Our findings indicate that hypomethylation of FKBP5 and retinoic acid receptor related genes serve a potential mechanistic explanation for long-lasting GC-induced psychopathology.

Depression and fatigue have previously been suggested to share an underlying genetic contribution. The present study aims to investigate and characterize the familiality and genetic relationship between depression and fatigue. The familiality of depression and fatigue was assessed by calculating relative risks, measured by the prevalence ratio, within 643 monozygotic (MZ) and 577 dizygotic (DZ) twin pairs. Bivariate twin modeling was utilized to assess the magnitude of shared heritability between depression and fatigue. Finally, the relationship between depression and fatigue was investigated using the co-twin control method, to determine whether the association is explained by causal or non-causal models. We observed an increased risk of fatigue in co-twins of probands with depression and increased risk of depression in co-twins of probands with fatigue. Higher risks were observed in MZ compared to DZ twin pairs, and bivariate heritability analyses indicated significant genetic components for depression and fatigue, with heritability estimates of 48% and 41%, respectively. Importantly, a significant additive genetic correlation of 0.71 [95% CI = 0.51-0.92) and bivariate heritability of 21% [95% CI = 10-35%] was observed between depression and fatigue. Furthermore, results from the co-twin control method indicate a non-causal genetic relationship that likely explains the association between depression and fatigue. Notably, the contribution of shared genetic factors remained significant, independent of the overlapping symptoms, indicating that the relationship between co-occurring depression and fatigue is primarily due to shared genetic factors rather than overlapping symptomatology.

Background: Chronic widespread muscoloskeletal pain (CWP) is prevalent in the general population and associated with high health care costs, so understanding the risk factors for chronic pain is important for both those affected and for society. In the present study we investigated the underlying etiological structure of CWP to understand better the association between the major clinical features of fatigue, depression and dihydroepiandrosterone sulphate (DHEAS) using a multivariate twin design., Methodology/principle Findings: Data were available in 463 UK female twin pairs including CWP status and information on depression, chronic fatigue and serum DHEAS levels. High to moderate heritabilities for all phenotypes were obtained (42.58% to 74.24%). The highest phenotypic correlation was observed between fatigue and CWP (r = 0.45), and the highest genetic correlation between CWP and fatigue (rg = 0.78). Structural equation modeling revealed the AE Cholesky model to provide the best model of the observed data. In this model, two additive genetic factors could be detected loading heavily on CWP-A2 explaining 40% of the variance and A3 20%. The factor loading heaviest on DHEAS showed only a small loading on the other phenotypes and none on fatigue at all. Furthermore, one distinct non-shared environmental factor loading specifically on CWP-but not on any of the other phenotypes-could be detected suggesting that the association between CWP and the other phenotypes is due only to genetic factors., Conclusions/significance: Our results suggest that CWP and its associated features share a genetic predisposition but that they are relatively distinct in their environmental determinants.

Pain, fatigue, sleep disturbance, and depression are common and frequently co-occurring symptoms in oncology patients. This symptom cluster is often attributed to the release of proinflammatory cytokines. The purposes of this study were to determine whether distinct latent classes of patients with breast cancer (n = 398) could be identified based on their experience with this symptom cluster, whether patients in these latent classes differed on demographic and clinical characteristics and whether variations in cytokine genes were associated with latent class membership. Three distinct latent classes were identified: "all low" (61.0%), "low pain and high fatigue" (31.6%), "all high" (7.1%). Compared to patients in the all low class, patients in the all high class were significantly younger, had less education, were more likely to be non-White, had a lower annual income, were more likely to live alone, had a lower functional status, had a higher comorbidity score, and had more advanced disease. Significant associations were found between interleukin 6 (IL6) rs2069845, IL13 rs1295686, and tumor necrosis factor alpha rs18800610 and latent class membership. Findings suggest that variations in pro- and anti-inflammatory cytokine genes are associated with this symptom cluster in breast cancer patients., (© The Author(s) 2014.)

Background: There is compelling evidence of a genetic foundation of patient-reported quality of life (QOL). Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010., Objectives: The objective was to provide an updated overview of the biological pathways, candidate genes, and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL., Methods: We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains., Results: Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception, and the catechol-O-methyltransferase (COMT) gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL., Conclusions: Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients' QOL.

Purpose: Symptom clusters, the multiple, co-occurring symptoms experienced by cancer patients, are debilitating and affects quality of life. We assessed if a panel of immune-response genes may underlie the co-occurrence of severe pain, depressed mood, and fatigue and help identify patients with severe versus non-severe symptom clusters., Methods: Symptoms were assessed at presentation, prior to cancer treatment in 599 newly diagnosed lung cancer patients. We applied cluster analyses to determine the patients with severe versus non-severe symptom clusters of pain, depressed mood, and fatigue., Results: Two homogenous clusters were identified. One hundred sixteen patients (19 %) comprised the severe symptom cluster, reporting high intensity of pain, depressed mood, and fatigue and 183 (30 %) patients reported low intensity of these symptoms. Using Bayesian model averaging methodology, we found that of the 55 single nucleotide polymorphisms assessed, an additive effect of mutant alleles in endothelial nitric oxide synthase (-1474 T/A) (posterior probability of inclusion (PPI) = 0.78, odds ratio (OR) = 0.54, 95 % credible interval (CI) = (0.31, 0.93)); IL1B T-31C (PPI = 0.72, OR = 0.55, 95 % CI = (0.31, 0.97)); TNFR2 Met(196)Arg (PPI = 0.70, OR = 1.85, 95 % CI = (1.03, 3.36)); PTGS2 exon 10+837T > C (PPI = 0.69, OR = 0.54, 95 % CI = (0.28, 0.99)); and IL10RB Lys(47)Glu (PPI = 0.68; OR = 1.74; 95 % CI = (1.04, 2.92)) were predictive for symptom clusters., Conclusions: Genetic polymorphisms may facilitate identification of high-risk patients and development of individualized symptom therapies.

Background: Cytokines and serotonin neurotransmission may play an important role on the development of psychopathological symptoms during interferon (IFN) treatment. The aim of the present study was to investigate the association between IFN-induced depression, anxiety and fatigue and functional genetic variants at the interleukin-6 gene (IL-6) and serotonin transporter gene (SERT)., Methods: 385 consecutive Caucasian outpatients with chronic hepatitis C initiating treatment with IFN-alpha and ribavirin were included. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV (SCID-I) and those with a current major depressive disorder or anxiety disorder before starting treatment were excluded. Depression and anxiety were assessed at baseline during the treatment (at 4, 12, 24 and 48 weeks) using the Hospital Anxiety and Depression Scale and fatigue was evaluated using a visual analogue scale. The 5-HTTLPR region of SERT gene and the functional polymorphism located at the promoter region of IL-6 gene (rs1800795) were genotyped., Results: Genotypic distribution was in the Hardy-Weinberg equilibrium for SERT (p=0.41) and for IL-6 (p=0.72) polymorphisms. At baseline we found only a significant effect of IL-6 polymorphism on fatigue symptoms. During antiviral treatment we reported that subjects with CC genotype (IL-6) presented significantly lower changes from baseline in IFN-induced depression (p=0.005) and IFN-induced anxiety (p=0.004). We did not find statistically significant differences on depression (p=0.21) or anxiety (p=0.15) between SS/SL and LL genotypes of SERT., Conclusions: Genetic variations in the IL-6 gene increase the risk of IFN-induced depression and anxiety. The IL-6 polymorphism was associated with fatigue rates in patients with chronic hepatitis C before treatment. Our study confirms the role of inflammatory mechanisms in IFN-induced psychopathological symptoms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Context: A report by the National Cancer Institute identified that an important gap in symptom research is the investigation of multiple symptoms of cancer that might identify common biological mechanisms among cancer-related symptoms., Objectives: We applied novel statistical methods to assess whether variants of 37 inflammation genes may serve as biologic markers of risk for severe pain, depressed mood, and fatigue in non-Hispanic white patients with non-small cell lung cancer., Methods: Pain, fatigue, and depressed mood were assessed before cancer treatment. We used a generalized, multivariate, classification tree approach to explore the influence of single-nucleotide polymorphisms in the inflammation genes in pain, depressed mood, and fatigue in lung cancer patients., Results: Among patients with advanced-stage disease, interleukin (IL)-8-T251A was the most relevant genetic factor for pain (odds ratio [OR] = 2.18, 95% CI = 1.34-3.55, P = 0.001), depressed mood (OR = 0.37, 95% CI = 0.14-1.0), and fatigue (OR = 2.07, 95% CI = 1.16-3.70). Among those with early-stage non-small cell lung cancer, variants in the IL-10 receptor were relevant for fatigue among women. Specifically, women with Lys&#95;Glu or Glu&#95;Glu genotype in the IL-10 gene had a 0.49 times lower risk of severe fatigue compared with those with Lys&#95;Lys genotype (OR = 0.49, 95% CI = 0.25-0.92, P = 0.027). Among men with early-stage lung cancer, a marginal significance was observed for IL-1A C-889T, C/T, or T/T genotypes. These men had a lower risk of severe fatigue compared with those with C/C genotype (OR = 0.38, 95% CI = 0.13-1.06)., Conclusion: The interaction of multiple inflammation genes, along with nongenetic factors, underlies the occurrence of symptoms. IL-8 and IL-10 may serve as potential targets for treating multiple symptoms of cancer., (Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.)

Background: Interferon-alpha (IFN-α) treatment for infectious disease and cancer causes high rates of depression and fatigue, and has been used to investigate the impact of inflammatory cytokines on brain and behavior. However, little is known about the transcriptional impact of chronic IFN-α on immune cells in vivo and its relationship to IFN-α-induced behavioral changes., Method: Genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells (PBMCs) from 21 patients with chronic hepatitis C virus (HCV) either awaiting IFN-α therapy (n=10) or at 12 weeks of IFN-α treatment (n=11)., Results: Significance analysis of microarray data identified 252 up-regulated and 116 down-regulated gene transcripts. Of the up-regulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2), a gene linked to chronic fatigue syndrome (CFS), was the only gene that was differentially expressed in patients with IFN-α-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks (r=0.80, p=0.003 and r=0.70, p=0.017 respectively). Promoter-based bioinformatic analyses linked IFN-α-related transcriptional alterations to transcription factors involved in myeloid differentiation, IFN-α signaling, activator protein-1 (AP1) and cAMP responsive element binding protein/activation transcription factor (CREB/ATF) pathways, which were derived primarily from monocytes and plasmacytoid dendritic cells. IFN-α-treated patients with high depression/fatigue scores demonstrated up-regulation of genes bearing promoter motifs for transcription factors involved in myeloid differentiation, IFN-α and AP1 signaling, and reduced prevalence of motifs for CREB/ATF, which has been implicated in major depression., Conclusions: Depression and fatigue during chronic IFN-α administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.

Because multiple symptoms associated with "sickness behavior" have a negative impact on functional status and quality of life, increased information on the mechanisms that underlie inter-individual variability in this symptom experience is needed. The purposes of this study were to determine: if distinct classes of individuals could be identified based on their experience with pain, fatigue, sleep disturbance, and depression; if these classes differed on demographic and clinical characteristics; and if variations in pro- and anti- inflammatory cytokine genes were associated with latent class membership. Self-report measures of pain, fatigue, sleep disturbance, and depression were completed by 168 oncology outpatients and 85 family caregivers (FCs). Using latent class profile analysis (LCPA), three relatively distinct classes were identified: those who reported low depression and low pain (83%), those who reported high depression and low pain (4.7%), and those who reported high levels of all four symptoms (12.3%). The minor allele of IL4 rs2243248 was associated with membership in the "All high" class along with younger age, being White, being a patient (versus a FC), having a lower functional status score, and having a higher number of comorbid conditions. Findings suggest that LPCA can be used to differentiate distinct phenotypes based on a symptom cluster associated with sickness behavior. Identification of distinct phenotypes provides new evidence for the role of IL4 in the modulation of a sickness behavior symptom cluster in oncology patients and their FCs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.

Introduction: Some hypothyroid patients continue to have significant impairments in psychological well-being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood-brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood-brain barrier, is considered to play a key role in delivering serum T4 to the brain., Objective: To examine whether polymorphisms in OATP1C1 are determinants of well-being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3)., Design and Participants: We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4-LT3 combination therapy., Outcome Measurements: Different questionnaires on well-being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1-intron3C > T, OATP1C1-Pro143Thr and OATP1C1-C3035T polymorphisms were determined., Results: Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1-intron3C > T and the OATP1C1-C3035T polymorphism, but not the OATP1C1-Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4-LT3 therapy., Conclusions: OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4-LT3 combination therapy. Future studies are needed to confirm these findings.

In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p<0.001) to levels reported by healthy subjects.