Abstract
The genetic background of pain is becoming increasingly well understood, which opens up possibilities for predicting the individual risk of persistent pain and the use of tailored therapies adapted to the variant pattern of the patient’s pain-relevant genes. The individual variant pattern of pain-relevant genes is accessible via next-generation sequencing, although the analysis of all “pain genes” would be expensive. Here, we report on the development of a cost-effective next generation sequencing-based pain-genotyping assay comprising the development of a customized AmpliSeq™ panel and bioinformatics approaches that condensate the genetic information of pain by identifying the most representative genes. The panel includes 29 key genes that have been shown to cover 70% of the biological functions exerted by a list of 540 so-called “pain genes” derived from transgenic mice experiments. These were supplemented by 43 additional genes that had been independently proposed as relevant for persistent pain. The functional genomics covered by the resulting 72 genes is particularly represented by mitogen-activated protein kinase of extracellular signal-regulated kinase and cytokine production and secretion. The present genotyping assay was established in 61 subjects of Caucasian ethnicity and investigates the functional role of the selected genes in the context of the known genetic architecture of pain without seeking functional associations for pain. The assay identified a total of 691 genetic variants, of which many have reports for a clinical relevance for pain or in another context. The assay is applicable for small to large-scale experimental setups at contemporary genotyping costs.
Highlights
A genetic background of pain plays a role in rare hereditary extreme phenotypes that cause either pain insensitivity [1] or paroxysmal pain disorders [2], in the perception of acute pain [3], in the risk of pain persistence after a triggering event [4], or in the response to pharmacological [5] or non-pharmacological [6] pain treatments
The functional genomics-based architecture of pain has been presented as a polyhierarchy of biological processes [8] based on the organization of the Gene Ontology knowledge base that captures the current knowledge about the biological roles of all genes and their respective products [18,19]
The NGS assay of the proposed set of 72 human genes relevant for persistent pain, was established in 61 genomic DNA samples available from a cohort of patients after breast cancer surgery [94] and including 55 subjects without pain and six patients with persistent pain, which corresponded to the ratio of persistent pain versus no pain in the entire cohort in order to resemble a random sample of subjects in terms of pain as much as possible
Summary
A genetic background of pain plays a role in rare hereditary extreme phenotypes that cause either pain insensitivity [1] or paroxysmal pain disorders [2], in the perception of acute pain [3], in the risk of pain persistence after a triggering event [4], or in the response to pharmacological [5] or non-pharmacological [6] pain treatments. With predominantly small effects exerted by common genetic variants [11], a breakthrough in the genetic profiling of individual risks, as occasionally expected [12], has not yet really been achieved [13]. Instead, this seems to be linked to a complex pattern of functional genetic variants [14], which is being discovered in an evolutionary rather than revolutionary way, which is supported by technical advances over the last decade [15] that allow to establish genotype versus phenotype associations for thousands of genetic variants in a still manageable small number of patients [14,16]. With the 29 genes, a respective representation created with 540 pain-relevant genes could be reconstructed by
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