Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1

F.M. Kirby Neurobiology Centre, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Brain (Impact Factor: 9.2). 09/2010; 133(9):2519-27. DOI: 10.1093/brain/awq195
Source: PubMed


Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.

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    • "Microarrays have been used extensively to investigate transcriptional changes that occur in different parts of the central and peripheral nervous systems [4]. Such studies have led to the discovery of novel pain-related genes, such as the Potassium voltage-gated channel subfamily S member 1, KCNS1 [2], GTP cyclohydrolase 1, GCH1 [6] and the neuropeptide VGF nerve growth factor inducible [7]. In recent years RNA-sequencing (RNA-seq) has emerged as an alternative platform for high-throughput transcriptional profiling [8]. "
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    ABSTRACT: The past decade has seen an abundance of transcriptional profiling studies of preclinical models of persistent pain, predominantly employing microarray technology. In this study we directly compare exon microarrays to RNA-seq and investigate the ability of both platforms to detect differentially expressed genes following nerve injury using the L5 spinal nerve transection model of neuropathic pain. We also investigate the effects of increasing RNA-seq sequencing depth. Finally we take advantage of the "agnostic" approach of RNA-seq to discover areas of expression outside of annotated exons that show marked changes in expression following nerve injury. RNA-seq and microarrays largely agree in terms of the genes called as differentially expressed. However, RNA-seq is able to interrogate a much larger proportion of the genome. It can also detect a greater number of differentially expressed genes than microarrays, across a wider range of fold changes and is able to assign a larger range of expression values to the genes it measures. The number of differentially expressed genes detected increases with sequencing depth. RNA-seq also allows the discovery of a number of genes displaying unusual and interesting patterns of non-exonic expression following nerve injury, an effect that cannot be detected using microarrays. We recommend the use of RNA-seq for future high-throughput transcriptomic experiments in pain studies. RNA-seq allowed the identification of a larger number of putative candidate pain genes than microarrays and can also detect a wider range of expression values in a neuropathic pain model. In addition, RNA-seq can interrogate the whole genome regardless of prior annotations, being able to detect transcription from areas of the genome not currently annotated as exons. Some of these areas are differentially expressed following nerve injury, and may represent novel genes or isoforms. We also recommend the use of a high sequencing depth in order to detect differential expression for genes with low levels of expression.
    Full-text · Article · Jan 2014 · Molecular Pain
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    • "with decreased electrical pain sensitivity and increased m-opioid analgesia Mogil et al. (2003) (2005), Liem et al. (2005) eLS & 2013, John Wiley & Sons, Ltd. 2. MC1R genotype significantly associated with higher levels of pentazocine analgesia in women but not men 3. MCR1 genotype more sensitive to thermal pain and resistant to the analgesic effects of lignocaine SCN9A Na v 1.7 sodium channel rs6746030 EXP Significant association between SCN9A polymorphism and experimental pain measures evoked by C-fibre activation Reimann et al. (2010) CLIN Significant association between SCN9A polymorphism and pain perception in patients with five different chronic pain conditions Reimann et al. (2010) Significant association between SCN9A polymorphism and pain perception in patients with multiple regional pain, but not osteoarthritic pain Valdes et al. (2011) KCNS1 Kv9.1 potassium channel rs734784 EXP Significant association between rs734784 and aggregate pain score calculated over 16 pain modalities Costigan et al. (2010) CLIN Significant association between KCNS1 polymorphism and pain intensity observed in cohorts of various clinical pain conditions Costigan et al. (2010) "

    Full-text · Chapter · Dec 2013
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    • "Furthermore, 124 co-regulated genes were identified in 3 neuropathic pain models (spared nerve injury, chronic construction injury, and spinal nerve ligation) by gene expression profiling of the rat dorsal root ganglion (DRG). Additionally, following a microarray-based screening study in large international pain cohort [5], a genetic association study was performed using single nucleotide polymorphisms (SNPs) of the potassium channel alpha subunit, KCNS1. "
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    ABSTRACT: Complex regional pain syndrome (CRPS) is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II) and 5 controls (cut-off value: 1.5-fold change and p<0.05). Most of those genes were associated with signal transduction, developmental processes, cell structure and motility, and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1), matrix metalloproteinase 9 (MMP9), alanine aminopeptidase N (ANPEP), l-histidine decarboxylase (HDC), granulocyte colony-stimulating factor 3 receptor (G-CSF3R), and signal transducer and activator of transcription 3 (STAT3) genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We focused on the MMP9 gene that, by qRT-PCR, showed a statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change (4.0±1.23 times and p = 1.4×10(-4)). The up-regulation of MMP9 gene in the blood may be related to the pain progression in CRPS patients. Our findings, which offer a valuable contribution to the understanding of the differential gene expression in CRPS may help in the understanding of the pathophysiology of CRPS pain progression.
    Full-text · Article · Nov 2013 · PLoS ONE
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