Pain perception is altered by a nucleotide polymorphism in SCN9A.
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.
Reimann
Frank
F
Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom.
Cox
James J
JJ
Belfer
Inna
I
Diatchenko
Luda
L
Zaykin
Dmitri V
DV
McHale
Duncan P
DP
Drenth
Joost P H
JP
Dai
Feng
F
Wheeler
Jerry
J
Sanders
Frances
F
Wood
Linda
L
Wu
Tian-Xia
TX
Karppinen
Jaro
J
Nikolajsen
Lone
L
Männikkö
Minna
M
Max
Mitchell B
MB
Kiselycznyk
Carly
C
Poddar
Minakshi
M
Te Morsche
Rene H M
RH
Smith
Shad
S
Gibson
Dustin
D
Kelempisioti
Anthi
A
Maixner
William
W
Gribble
Fiona M
FM
Woods
C Geoffrey
CG
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*
D050505:Mutant Proteins; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels