Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1
Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1
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DOI：
10.1093/brain/awq195
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发表时间：
2010-09-01
期刊：
影响因子：
14.5
通讯作者：
woolf, Clifford J.
中科院分区：
文献类型：
--
作者：
Costigan, Michael;Belfer, Inna;woolf, Clifford J.
并不是所有的神经损伤患者都会出现神经病理性疼痛。神经损伤的程度和受伤时的年龄是迄今为止确定的为数不多的风险因素中的两个。此外，临床前研究表明神经病理性疼痛的变异是可遗传的。为了进一步确定这些因素，我们进行了一项大规模的基因图谱实验，绘制了三种周围神经病理性疼痛模型中大鼠背根神经节的整体表达变化。结果发现，参与神经元兴奋性的钾通道α亚基KCNS1在感觉神经元中结构性表达，并在神经损伤后显著下调。然后，KCNS1被无偏网络分析确定为假定的疼痛基因，这一结果得到了人类单核苷酸多态关联研究的证实。在六个独立的患者队列中(总共1359名受试者)，一种常见的氨基酸变化等位基因--Valine风险等位基因--与较高的疼痛评分显著相关。风险等位基因的患病率很高，有18%-22%的人群是纯合子，另外还有50%是杂合子。在神经损伤程度较低(腰背部疼痛伴腰椎间盘突出)的纯合子患者中，与更大疼痛结局相关的P=0.003，如果神经损伤程度较高(截肢)，则增加到P=0.0001。在所有测试的六个队列中，疼痛关联的综合P值为1.14 E-08。这个标记的风险概况是累加的：两个副本授予最大的风险，一个副本授予中等风险，一个副本授予最小的风险。风险增加的相对程度在不同的队列中有所不同，但对于腰背痛的患者，风险增加的程度在2到3倍之间。尽管仍有工作要确定这种蛋白在发病过程中的潜在作用，但在这里，我们将KCNS1等位基因rs734784作为慢性疼痛风险的第一个预后指标之一。对该等位基因的筛查可以帮助确定那些容易过渡到持续性疼痛的人，因此需要治疗策略或生活方式的改变，以将神经损伤降至最低。
Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.