Using Gene Expression Signatures to Identify Novel Treatment Strategies in Gulf War Illness

Background Gulf War Illness (GWI) is a complex multi-symptom disorder that affects up to one in three veterans of this 1991 conflict and for which no effective treatment has been found. Discovering novel treatment strategies for such a complex chronic illness is extremely expensive, carries a high probability of failure and a lengthy cycle time. Repurposing Food and Drug Administration approved drugs offers a cost-effective solution with a significantly abbreviated timeline. Methods Here, we explore drug re-purposing opportunities in GWI by combining systems biology and bioinformatics techniques with pharmacogenomic information to find overlapping elements in gene expression linking GWI to successfully treated diseases. Gene modules were defined based on cellular function and their activation estimated from the differential expression of each module’s constituent genes. These gene modules were then cross-referenced with drug atlas and pharmacogenomic databases to identify agents currently used successfully for treatment in other diseases. To explore the clinical use of these drugs in illnesses similar to GWI we compared gene expression patterns in modules that were significantly expressed in GWI with expression patterns in those same modules in other illnesses. Results We found 19 functional modules with significantly altered gene expression patterns in GWI. Within these modules, 45 genes were documented drug targets. Illnesses with highly correlated gene expression patterns overlapping considerably with GWI were found in 18 of the disease conditions studied. Brain, muscular and autoimmune disorders composed the bulk of these. Conclusion Of the associated drugs, immunosuppressants currently used in treating rheumatoid arthritis, and hormone based therapies were identified as the best available candidates for treating GWI symptoms

Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS) is a complex, multi-symptom illness with a multisystem pathogenesis involving alterations in the nervous, endocrine and immune systems.</p> <p>Abnormalities in stress responses have been identified as potential triggers or mediators of CFS symptoms. This study focused on the stress mediator neuropeptide Y (NPY). We hypothesized that NPY would be a useful biomarker for CFS.</p> <p>Methods</p> <p>The CFS patients (n = 93) were from the Chronic Fatigue and Related Disorders Clinic at the University of Miami and met the 1994 case definition of Fukuda and colleagues. Healthy sedentary controls (n = 100)) were from NIH or VA funded studies. Another fatiguing, multi-symptom illness, Gulf War Illness (GWI), was also compared to CFS. We measured NPY in plasma using a radioimmunoassay (RIA). Psychometric measures, available for a subset of CFS patients included: Perceived Stress Scale, Profile of Mood States, ATQ Positive & Negative Self-Talk Scores, the COPE, the Beck Depression Inventory, Fatigue Symptom Inventory, Cognitive Capacity Screening Examination, Medical Outcomes Survey Short Form-36, and the Quality of Life Scale.</p> <p>Results</p> <p>Plasma NPY was elevated in CFS subjects, compared to controls (p = .000) and to GWI cases (p = .000). Receiver operating characteristics (ROC) curve analyses indicated that the predictive ability of plasma NPY to distinguish CFS patients from healthy controls and from GWI was significantly better than chance alone. In 42 patients with CFS, plasma NPY had significant correlations (<0.05) with perceived stress, depression, anger/hostility, confusion, negative thoughts, positive thoughts, general health, and cognitive status. In each case the correlation (+ or -) was in the anticipated direction.</p> <p>Conclusions</p> <p>This study is the first in the CFS literature to report that plasma NPY is elevated compared to healthy controls and to a fatigued comparison group, GWI patients. The significant correlations of NPY with stress, negative mood, general health, depression and cognitive function strongly suggest that this peptide be considered as a biomarker to distinguish subsets of CFS.</p

Illness progression in chronic fatigue syndrome: a shifting immune baseline.

BACKGROUND: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness. METHODS: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18–50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori. RESULTS: Optimal selection of cytokines in each group resulted in subsets of IL-1α, 6, 8, 15 and TNFα. Common to any 2 of 3 groups were IL-1α, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub-groups produced ME/CFS classification accuracies of 75–88 %. The contribution of IL-1α, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years. CONCLUSIONS: These preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-016-0142-3) contains supplementary material, which is available to authorized users