title: Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.
abstract: 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.
authors: F.M. Kirby Neurobiology Centre, Children’s Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
authors: Michael
authors: M
authors: Costigan
authors: Inna
authors: I
authors: Belfer
authors: Robert S
authors: RS
authors: Griffin
authors: Feng
authors: F
authors: Dai
authors: Lee B
authors: LB
authors: Barrett
authors: Giovanni
authors: G
authors: Coppola
authors: Tianxia
authors: T
authors: Wu
authors: Carly
authors: C
authors: Kiselycznyk
authors: Minakshi
authors: M
authors: Poddar
authors: Yan
authors: Y
authors: Lu
authors: Luda
authors: L
authors: Diatchenko
authors: Shad
authors: S
authors: Smith
authors: Enrique J
authors: EJ
authors: Cobos
authors: Dmitri
authors: D
authors: Zaykin
authors: Andrew
authors: A
authors: Allchorne
authors: Edith
authors: E
authors: Gershon
authors: Jessica
authors: J
authors: Livneh
authors: Pei-Hong
authors: PH
authors: Shen
authors: Lone
authors: L
authors: Nikolajsen
authors: Jaro
authors: J
authors: Karppinen
authors: Minna
authors: M
authors: Männikkö
authors: Anthi
authors: A
authors: Kelempisioti
authors: David
authors: D
authors: Goldman
authors: William
authors: W
authors: Maixner
authors: Daniel H
authors: DH
authors: Geschwind
authors: Mitchell B
authors: MB
authors: Max
authors: Ze'ev
authors: Z
authors: Seltzer
authors: Clifford J
authors: CJ
authors: Woolf
mesh_terms: D000818:Animals; D002908:Chronic Disease; D015331:Cohort Studies; D032882:Comprehension; D019295:Computational Biology / Q000379:methods; D003431:Cross-Cultural Comparison; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D016900:Neurofilament Proteins; D009479:Neuropeptides / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010146:Pain / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D051381:Rats; D014633:Valine / Q000235:genetics*
chemical_list: C496946:KCNA1 protein, human; D016900:Neurofilament Proteins; D009479:Neuropeptides; C051774:neurofilament protein H; D051662:Kv1.1 Potassium Channel; D014633:Valine