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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pain perception is altered by a nucleotide polymorphism in SCN9A
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Pain perception is altered by a nucleotide polymorphism in SCN9A

机译：疼痛感知被SCN9A中的核苷酸多态性改变

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摘要

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 radio-graphic 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.
机译：SCN9A基因负责三种人类疼痛性疾病。无意义的突变会导致疼痛的完全消失，而激活性突变会导致阵发性极度疼痛和原发性红热病的严重发作性疼痛。这导致我们调查了SCN9A中的单核苷酸多态性（SNP）是否与普通人群中不同的疼痛感相关。我们首先对578名个体进行了27个SCN9A SNP基因分型，并进行了影像学诊断的骨关节炎和疼痛评分评估。发现疼痛评分与SNP rs6746030之间存在显着相关性。与普通的G等位基因相比，罕见的A等位基因与疼痛评分增加相关（P = 0.016）。然后，对195个坐骨神经痛进行疼痛评估的患者，100名幻影疼痛的截肢者，腰椎间盘切除术后的179个人以及205例胰腺炎进行了进一步的基因分型。在五个测试的队列中（共1277人），增加的A等位基因疼痛的P值合计为0.0001。 SNP rs6746030的两个等位基因改变了钠通道Nav1.7的编码序列。将它们各自分别转染到HEK293细胞中，并通过膜片钳进行电生理评估。这两个等位基因在电压依赖性慢灭活中表现出差异（P = 0.042），其中A等位基因可以预测增加Nav1.7活性。最后，我们对186名健康女性进行了基因分型，其特征是她们对各种有害刺激物的反应。 rs6746030的A等位基因与改变的疼痛阈值和通过C纤维激活介导的作用有关。我们得出的结论是，根据伤害性刺激，个体根据其SCN9A rs6746030基因型会经历不同程度的疼痛。

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    Frank Reimann; 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 Maennikkoe; Mitchell B. Max; Carly Kiselycznyk; Minakshi Poddar; Rene H.M. te Morsche; Shad Smith; Dustin Gibson; Anthi Kelempisioti; William Maixner; Fiona M. Gribble; C. Geoffrey Woods;

  • 作者单位

    Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom;

    rnDepartment of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 OXY, United Kingdom;

    rnMolecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;

    Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;

    rnNational Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;

    rnPfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, United Kingdom;

    rnDepartment of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands;

    rnMolecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261 Departments of Anesthesiology and Biostatistics and Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;

    rnPfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, United Kingdom;

    rnPfizer Global Research and Development, Sandwich Laboratories, Sandwich CT13 9NJ, United Kingdom;

    rnPfizer Global Research and Development, Groton Laboratories, Groton, CT 06340;

    rnCenter for Information Technology, National Institutes of Health, Bethesda, MD 20892;

    rnOulu Center for Cell-Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, FIN-90014 University of Oulu, Oulu, Finland;

    rnMusculoskeletal Centre, Finnish Institute of Occupational Health, and Institute of Clinical Sciences, Department of Physical Medicine and Rehabilitation, FI-90220 University of Oulu, Oulu, Finland;

    rnOulu Center for Cell-Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, FIN-90014 University of Oulu, Oulu, Finland;

    rnMolecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;

    rnCenter for Information Technology, National Institutes of Health, Bethesda, MD 20892;

    rnMolecular Epidemiology of Pain Program, Department of Anaesthesiology, University of Pittsburgh, Pittsburgh, PA 15261;

    rnDepartment of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands;

    rnCenter for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;

    rnCenter for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;

    rnOulu Center for Cell-Matrix Research, Biocenter and Department of Medical Biochemistry and Molecular Biology, FIN-90014 University of Oulu, Oulu, Finland;

    rnCenter for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455;

    rnDepartment of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 OXY, United Kingdom;

    rnDepartment of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge CB2 0XY, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    Na_v1.7; nociception; pain; SCN9A; single nucleotide polymorphisms;

    机译：Na_v1.7;伤害感受痛;SCN9A;单核苷酸多态性;

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