{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:04:37Z","timestamp":1791313477000,"version":"4.3.1"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,3,16]]},"abstract":"<jats:p>\n                    The gene\n                    <jats:italic>SCN9A<\/jats:italic>\n                    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\n                    <jats:italic>SCN9A<\/jats:italic>\n                    were associated with differing pain perception in the general population. We first genotyped 27\n                    <jats:italic>SCN9A<\/jats:italic>\n                    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 (\n                    <jats:italic>P<\/jats:italic>\n                    = 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\n                    <jats:italic>P<\/jats:italic>\n                    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 (\n                    <jats:italic>P<\/jats:italic>\n                    = 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\n                    <jats:italic>SCN9A<\/jats:italic>\n                    rs6746030 genotype.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0913181107","type":"journal-article","created":{"date-parts":[[2010,3,9]],"date-time":"2010-03-09T00:29:02Z","timestamp":1268094542000},"page":"5148-5153","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":282,"title":["Pain perception is altered by a nucleotide polymorphism in\n                    <i>SCN9A<\/i>"],"prefix":"10.1073","volume":"107","author":[{"given":"Frank","family":"Reimann","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Belfer","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luda","family":"Diatchenko","sequence":"additional","affiliation":[{"name":"Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitri V.","family":"Zaykin","sequence":"additional","affiliation":[{"name":"National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan P.","family":"McHale","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost P. H.","family":"Drenth","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Dai","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;"},{"name":"Departments of Anesthesiology and Biostatistics and Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Sanders","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Wood","sequence":"additional","affiliation":[{"name":"Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Xia","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Information Technology, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaro","family":"Karppinen","sequence":"additional","affiliation":[{"name":"Oulu Center for Cell\u2013Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, FIN-90014 University of Oulu, Oulu, Finland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lone","family":"Nikolajsen","sequence":"additional","affiliation":[{"name":"Musculoskeletal Centre, Finnish Institute of Occupational Health, and Institute of Clinical Sciences, Department of Physical Medicine and Rehabilitation, FI-90220 University of Oulu, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"M\u00e4nnikk\u00f6","sequence":"additional","affiliation":[{"name":"Oulu Center for Cell\u2013Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, FIN-90014 University of Oulu, Oulu, Finland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell B.","family":"Max","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carly","family":"Kiselycznyk","sequence":"additional","affiliation":[{"name":"Center for Information Technology, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minakshi","family":"Poddar","sequence":"additional","affiliation":[{"name":"Molecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene H.M.","family":"te Morsche","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shad","family":"Smith","sequence":"additional","affiliation":[{"name":"Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin","family":"Gibson","sequence":"additional","affiliation":[{"name":"Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthi","family":"Kelempisioti","sequence":"additional","affiliation":[{"name":"Oulu Center for Cell\u2013Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, FIN-90014 University of Oulu, Oulu, Finland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Maixner","sequence":"additional","affiliation":[{"name":"Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"Gribble","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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