title: Pain perception is altered by a nucleotide polymorphism in SCN9A.
abstract: The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype.
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.forename: James J
authors.initials: JJ
authors.lastname: Cox
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Zaykin
authors.forename: Duncan P
authors.initials: DP
authors.lastname: McHale
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.forename: Jerry
authors.initials: J
authors.lastname: Wheeler
authors.forename: Frances
authors.initials: F
authors.lastname: Sanders
authors.forename: Linda
authors.initials: L
authors.lastname: Wood
authors.forename: Tian-Xia
authors.initials: TX
authors.lastname: Wu
authors.forename: Jaro
authors.initials: J
authors.lastname: Karppinen
authors.forename: Lone
authors.initials: L
authors.lastname: Nikolajsen
authors.forename: Minna
authors.initials: M
authors.lastname: Männikkö
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Max
authors.forename: Carly
authors.initials: C
authors.lastname: Kiselycznyk
authors.forename: Minakshi
authors.initials: M
authors.lastname: Poddar
authors.forename: Rene H M
authors.initials: RH
authors.lastname: Te Morsche
authors.forename: Shad
authors.initials: S
authors.lastname: Smith
authors.forename: Dustin
authors.initials: D
authors.lastname: Gibson
authors.forename: Anthi
authors.initials: A
authors.lastname: Kelempisioti
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
mesh_terms: D000328:Adult; D000483:Alleles; D055592:Biophysical Phenomena / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000235:genetics* / Q000503:physiopathology; D017288:Pain Threshold; D010465:Perception; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012044:Regression Analysis; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels