title: A SCN10A SNP biases human pain sensitivity.
abstract: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined.
  
  
  
  Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G > A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by -4.3 mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity.
  
  
  
  At the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity.
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.
authors: Guangyou
authors: G
authors: Duan
authors: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, CT, USA.
authors: Chongyang
authors: C
authors: Han
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China Department of Anesthesiology, Wuhan General Hospital of Guangzhou Military, Wuhan, P.R. China.
authors: Qingli
authors: Q
authors: Wang
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Shanna
authors: S
authors: Guo
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Yuhao
authors: Y
authors: Zhang
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Ying
authors: Y
authors: Ying
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Penghao
authors: P
authors: Huang
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Li
authors: L
authors: Zhang
authors: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, CT, USA.
authors: Lawrence
authors: L
authors: Macala
authors: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, CT, USA.
authors: Palak
authors: P
authors: Shah
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Mi
authors: M
authors: Zhang
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Ningbo
authors: N
authors: Li
authors: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, CT, USA.
authors: Sulayman D
authors: SD
authors: Dib-Hajj
authors: Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Rehabilitation Research Center, Veterans' Affairs Connecticut Healthcare System, West Haven, CT, USA stephen.waxman@yale.edu ourpain@163.com.
authors: Stephen G
authors: SG
authors: Waxman
authors: Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors: Xianwei
authors: X
authors: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D010146:Pain / Q000209:etiology / Q000235:genetics*; D058748:Pain Perception / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011930:Reaction Time / Q000235:genetics; D055815:Young Adult
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human
keywords: Nav1.8; dorsal root ganglion; pain; voltage-gated sodium channel