Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs
Ontology highlight
ABSTRACT: We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful withinsubject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis.
Project description:The biological fingerprint of environmental adversity may be key to understanding health and disease, as it encompasses the damage induced as well as the compensatory reactions of the organism. Metabolic and hormonal changes may be an informative but incomplete window into the underlying biology. We endeavored to identify objective blood gene expression biomarkers for psychological stress, a subjective sensation with biological roots. To quantify the stress perception at a particular moment in time, we used a simple visual analogue scale for life stress in psychiatric patients, a high risk group. Then, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design, we were successful in identifying gene expression biomarkers that were predictive of high stress states, and of future psychiatric hospitalizations related to stress, more so when personalized by gender and diagnosis.
Project description:Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole blood DNA methylation was characterized at 5.2 million loci by MeDIP-sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain-sensitivity (pain-DMRs). Nine meta-analysis pain-DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2M-CM-^W10-13). Several pain-DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in brain, and altered expression in skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits. MeDIP-sequencing in 100 individulas using a 2 stage design: paired-end MeDIP-seq in 50 monozygotic twins and single-end MeDIP-seq in 50 unrelated individuals.
Project description:Pain is a subjective experience derived from complex interactions among biological, environmental, and psychosocial pathways. Sex differences in pain sensitivity and chronic pain prevalence are well established. However, the molecular causes underlying these sex dimorphisms are poorly understood particularly with regard to the role of the peripheral nervous system. Here we sought to identify shared and distinct gene networks functioning in the peripheral nervous systems that may contribute to sex differences of pain after nerve injury. We performed RNA-seq on dorsal root ganglia following chronic constriction injury of the sciatic nerve in male and female rats. Analysis from paired naive and injured tissues showed that 1456 genes were differentially expressed between sexes. Appreciating sex-related gene expression differences and similarities in neuropathic pain models may help to improve the translational relevance to clinical populations and efficacy of clinical trials of this major health issue.
Project description:Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) Methods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR. Findings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of M-bM-^@M-^\The co-stimulatory signaling during T cell activationM-bM-^@M-^] Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction. Interpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF. They should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies. This submission represents the Affymetrix component of the study (discovery cohort)
Project description:Pain management is an important issue in veterinary medicine, requiring biomarkers with high sensitivity and specificity for the timely and effective treatment. Emerging evidence suggests that miRNAs are promising pain-related markers. The aims were to profile the circulating miRNA signature in plasma of turtles (Trachemys scripta) and point out potential candidate biomarkers of pain. Plasma of female turtles underwent surgical gonadectomy were collected 24h pre-surgery, and 2.5h and 36 h post-surgery. The expression of miRNAs was profiled by Next Generation Sequencing and the dysregulated miRNAs were validated using RT-qPCR. The diagnostic value of miRNAs was calculated by ROC curves.
Project description:Fibromyalgia (FM) is a chronic pain condition and consists of widespread pain with similarities to neuropathic pain in clinical findings, pathophysiology, and neuropharmacology. Its mechanisms are poorly understood and a lack of effective biomarkers for diagnosis and onset prediction. This study aimed to identify the metabolites to characterize pain and sngception (Sng) in FM.