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

Publication ,  Journal Article
Costigan, M; Belfer, I; Griffin, RS; Dai, F; Barrett, LB; Coppola, G; Wu, T; Kiselycznyk, C; Poddar, M; Lu, Y; Diatchenko, L; Smith, S ...
Published in: Brain
September 2010

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.

Duke Scholars

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Published In

Brain

DOI

EISSN

1460-2156

Publication Date

September 2010

Volume

133

Issue

9

Start / End Page

2519 / 2527

Location

England

Related Subject Headings

  • Valine
  • Rats
  • Polymorphism, Genetic
  • Pain
  • Oligonucleotide Array Sequence Analysis
  • Neuropeptides
  • Neurology & Neurosurgery
  • Neurofilament Proteins
  • Male
  • Linkage Disequilibrium
 

Citation

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Costigan, M., Belfer, I., Griffin, R. S., Dai, F., Barrett, L. B., Coppola, G., … Woolf, C. J. (2010). Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain, 133(9), 2519–2527. https://doi.org/10.1093/brain/awq195
Costigan, Michael, Inna Belfer, Robert S. Griffin, Feng Dai, Lee B. Barrett, Giovanni Coppola, Tianxia Wu, et al. “Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.Brain 133, no. 9 (September 2010): 2519–27. https://doi.org/10.1093/brain/awq195.
Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, et al. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain. 2010 Sep;133(9):2519–27.
Costigan, Michael, et al. “Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.Brain, vol. 133, no. 9, Sept. 2010, pp. 2519–27. Pubmed, doi:10.1093/brain/awq195.
Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, Wu T, Kiselycznyk C, Poddar M, Lu Y, Diatchenko L, Smith S, Cobos EJ, Zaykin D, Allchorne A, Gershon E, Livneh J, Shen P-H, Nikolajsen L, Karppinen J, Männikkö M, Kelempisioti A, Goldman D, Maixner W, Geschwind DH, Max MB, Seltzer Z, Woolf CJ. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain. 2010 Sep;133(9):2519–2527.
Journal cover image

Published In

Brain

DOI

EISSN

1460-2156

Publication Date

September 2010

Volume

133

Issue

9

Start / End Page

2519 / 2527

Location

England

Related Subject Headings

  • Valine
  • Rats
  • Polymorphism, Genetic
  • Pain
  • Oligonucleotide Array Sequence Analysis
  • Neuropeptides
  • Neurology & Neurosurgery
  • Neurofilament Proteins
  • Male
  • Linkage Disequilibrium