Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1

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.并非所有神经损伤患者都会罹患神经病理性疼痛（neuropathic pain）。截至目前，已明确的为数不多的风险因素包括神经损伤程度与损伤发生时的患者年龄。此外，临床前研究表明，神经病理性疼痛的个体差异具有遗传性。为进一步明确此类风险因素，本研究开展了大规模基因表达谱分析实验，对3种周围性神经病理性疼痛模型大鼠的背根神经节（dorsal root ganglion）进行了全基因表达变化检测。该实验发现，参与神经元兴奋性调控的钾通道α亚基KCNS1在感觉神经元中呈组成型表达，并在神经损伤后显著下调。随后通过无偏网络分析将KCNS1鉴定为潜在疼痛相关基因，这一结果在人类单核苷酸多态性（single nucleotide polymorphism）关联研究中得到了验证。一种常见的可导致氨基酸改变的等位基因——“缬氨酸风险等位基因”，在6个独立患者队列（共计1359名受试者）中的5个队列里，与更高的疼痛评分显著相关。该风险等位基因的携带率较高，人群中18%~22%为纯合子携带者，另有约50%为杂合子携带者。在神经损伤程度较轻的队列（椎间盘突出症相关腰背痛患者）中，纯合子携带者的疼痛程度更严重，关联分析P值为0.003；而在神经损伤程度较重的队列（肢体截肢患者）中，该关联的P值降至0.0001。所有6个受试队列的疼痛关联联合P值为1.14×10^-8。该分子标记的风险模式呈加性效应：携带2个风险等位基因者风险最高，1个者风险中等，无携带者风险最低。不同队列中风险升高的相对程度存在差异，但在腰背痛患者队列中，风险升高幅度为2~3倍。尽管目前仍需进一步阐明该蛋白在疼痛发生的病理过程中的潜在作用，但本研究将KCNS1等位基因rs734784列为首批慢性疼痛风险预后标志物之一。对该等位基因进行筛查，有助于识别易进展为持续性疼痛的人群，从而为其制定针对性治疗策略或调整生活方式，以最大限度降低神经损伤风险。