A machine‐learned analysis of human gene polymorphisms modulating persisting pain points to major roles of neuroimmune processes

Abstract

BackgroundHuman genetic research has implicated functional variants of more than one hundred genes in the modulation of persisting pain. Artificial intelligence and machine‐learning techniques may combine this knowledge with results of genetic research gathered in any context, which permits the identification of the key biological processes involved in chronic sensitization to pain.MethodsBased on published evidence, a set of 110 genes carrying variants reported to be associated with modulation of the clinical phenotype of persisting pain in eight different clinical settings was submitted to unsupervised machine‐learning aimed at functional clustering. Subsequently, a mathematically supported subset of genes, comprising those most consistently involved in persisting pain, was analysed by means of computational functional genomics in the Gene Ontology knowledgebase.ResultsClustering of genes with evidence for a modulation of persisting pain elucidated a functionally heterogeneous set. The situation cleared when the focus was narrowed to a genetic modulation consistently observed throughout several clinical settings. On this basis, two groups of biological processes, the immune system and nitric oxide signalling, emerged as major players in sensitization to persisting pain, which is biologically highly plausible and in agreement with other lines of pain research.ConclusionsThe present computational functional genomics‐based approach provided a computational systems‐biology perspective on chronic sensitization to pain. Human genetic control of persisting pain points to the immune system as a source of potential future targets for drugs directed against persisting pain. Contemporary machine‐learned methods provide innovative approaches to knowledge discovery from previous evidence.SignificanceWe show that knowledge discovery in genetic databases and contemporary machine‐learned techniques can identify relevant biological processes involved in Persitent pain.

Machine-learned analysis of global and glial/opioid intersection–related DNA methylation in patients with persistent pain after breast cancer surgery

“…Furthermore, since DNA methylation is tissue specific [74], a negative result obtained in DNA extracted from blood cells does not exclude an epigenetic modulation via TLR4 or OPRM1 in the central nervous system. Finally, the hypothesized epigenetic control of neuroimmune crosstalk in persistent pain remains a possibility via further genes involved in the glial-opioid interface [17].…”

“…The involvement of neuroimmune processes in persistent pain is under genetic control [17], suggesting that it may also be under epigenetic control. Indeed, classical epigenetic mechanisms including changes in DNA methylation and histone modifications have been shown to contribute to the development and treatment responsiveness of persistent pain [18].…”

Computational Functional Genomics-Based AmpliSeq™ Panel for Next-Generation Sequencing of Key Genes of Pain

“…A 72-pain gene NGS panel is proposed that covers (i) a subset of 29 genes identified previously in a bioinformatics approach as key genes covering the biological functions of 540 genes relevant to pain by 70% [ 17 ]. Additional genes that were included, had been independently proposed as relevant for persistent pain [ 9 , 10 ], and the functional focus of the whole panel was now on immune or inflammatory processes, in line with the increasing evidence that such processes are key players in persistent pain [ 115 ]. Together with a recently established AmpliSeq™ panel of 77 further pain-relevant genes [ 20 ], the assay covers a relevant part of the current state of knowledge on the genetic architecture of persistent pain ( Figure 1 ).…”

“…The approach to the functional genomics biological roles of the set of pain genes was the same as before for the complete set of pain genes [ 8 , 17 ], or for other contextually selected sets of genes relevant to pain [ 115 ]. The methods were described in detail in special publications [ 17 , 98 ].…”

Spared nerve injury causes sexually dimorphic mechanical allodynia and differential gene expression in spinal cords and dorsal root ganglia in rats

“…These cells can also in ltrate the spinal cord (SC) following PNI and play a role in pain hypersensitivity [10,16]. These and other neuroimmune processes, also studied in humans, are of great interest in explaining persistence of NP [17].…”