title: SCN9A Variants May be Implicated in Neuropathic Pain Associated With Diabetic Peripheral Neuropathy and Pain Severity.
abstract: OBJECTIVE
  Previous studies have established the role of SCN9A in various pain conditions, including idiopathic small fiber neuropathy. In the present study, we interrogate the relationship between common and rare variants in SCN9A gene and chronic neuropathic pain associated with diabetic peripheral neuropathy.
  
  
  METHODS
  Using a cohort of 938 patients of European ancestry with chronic neuropathic pain associated with diabetic peripheral neuropathy enrolled in 6 clinical studies and 2 controls (POPRES, n=2624 and Coriell, n=1029), we examined the relationship between SCN9A variants and neuropathic pain in a case-control study using a 2-stage design. The exonic regions of SCN9A were sequenced in a subset of 244 patients with neuropathic pain, and the variants discovered were compared with POPRES control (stage 1). The top associated variants were followed up by genotyping in the entire case collection and Coriell controls restricting the analysis to the matching patients from the United States and Canada only (stage 2).
  
  
  RESULTS
  Seven variants were found to be associated with neuropathic pain at the sequencing stage. Four variants (Asp1908Gly, Val991Leu/Met932Leu, and an intronic variant rs74449889) were confirmed by genotyping to occur at a higher frequency in cases than controls (odds ratios ∼2.1 to 2.6, P=0.05 to 0.009). Val991Leu/Met932Leu was also associated with the severity of pain as measured by pain score Numeric Rating Scale (NRS-11, P=0.047). Val991Leu/Met932Leu variants were in complete linkage disequilibrium and previously shown to cause hyperexcitability in dorsal root ganglia neurons.
  
  
  CONCLUSIONS
  The association of SCN9A variants with neuropathic pain and pain severity suggests a role of SCN9A in the disease etiology of neuropathic pain.
authors.affiliation: *Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Titusville †Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Raritan, NJ ‡Aranea, Janssen Research & Development, LLC, La Jolla, CA §Neuroscience Therapeutic Area, Janssen Research & Development, LLC, Spring House, PA.
authors.forename: Qingqin S
authors.initials: QS
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Cheng
authors.forename: Reyna
authors.initials: R
authors.lastname: Favis
authors.forename: Alan
authors.initials: A
authors.lastname: Wickenden
authors.forename: Gary
authors.initials: G
authors.lastname: Romano
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D002170:Canada; D059350:Chronic Pain / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D003929:Diabetic Neuropathies / Q000235:genetics* / Q000503:physiopathology; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D060005:Genotyping Techniques; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D009437:Neuralgia / Q000235:genetics* / Q000503:physiopathology; D010147:Pain Measurement; D012720:Severity of Illness Index; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human