Pain perception is altered by a nucleotide polymorphism in SCN9A

Frank Reimanna, James J. Cox, Inna Belfer, Luda Diatchenko, Dmitri V. Zaykin, Duncan P. McHale, Joost P.H. Drenth, Feng Dai, Jerry Wheeler, Frances Sanders, Linda Wood, Tian Xia Wu, Jaro Karppinen, Lone Nikolajsen, Minna Männikkö, Mitchell B. Max, Carly Kiselyczny, Minakshi Poddar, Rene H.M. Te Morsche, Shad SmithDustin Gibson, Anthi Kelempisioti, William Maixner, Fiona M. Gribble, C. Geoffrey Woods

Research output: Contribution to journalArticlepeer-review

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 Aallele pain was0.0001 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 Aallele 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.

Original languageEnglish (US)
Pages (from-to)5148-5153
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number11
DOIs
StatePublished - Mar 16 2010
Externally publishedYes

Keywords

  • Na1.7
  • Nociception
  • Pain
  • SCN9A
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • General

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