Faculty of Dental Medicine and Oral Health Sciences, Department of Anesthesia, Faculty of Medicine and Health Sciences, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
Department of Research, Innovation and Education, Oslo University Hospital, Oslo, Norway.
Pain. 2023 Aug 1;164(8):1841-1851. doi: 10.1097/j.pain.0000000000002882. Epub 2023 Mar 22.
Chronic pain is a prevalent disease with increasing clinical challenges. Genome-wide association studies in chronic pain patients have identified hundreds of common pathogenic variants, yet they only explained a portion of individual variance of chronic pain. With the advances in next-generation sequencing technologies, it is now feasible to conduct rarer variants studies in large-scale databases. Here, we performed gene-based rare variant analyses in 200,000 human subjects in the UK biobank whole-exome sequencing database for investigating 9 different chronic pain states and validated our findings in 3 other large-scale databases. Our analyses identified the SLC13A1 gene coding for sodium/sulfate symporter associated with chronic back pain and multisite pain at the genome-wide level and with chronic headache, knee, and neck and shoulder pain at the nominal level. Seven loss-of-function rare variants were identified within the gene locus potentially contributing to the development of chronic pain, with 2 of them individually associated with back pain and multisite pain. These 2 rare variants were then tested for replication in 3 other biobanks, and the strongest evidence was found for rs28364172 as an individual contributor. Transcriptional analyses of Slc13a1 in rodents showed substantial regulation of its expression in the dorsal root ganglia and the sciatic nerve in neuropathic pain assays. Our results stress the importance of the SLC13A1 gene in sulfate homeostasis in the nervous system and its critical role in preventing pain states, thus suggesting new therapeutic approaches for treating chronic pain in a personalized manner, especially in people with mutations in the SLC13A1 gene.
慢性疼痛是一种普遍存在的疾病，具有日益增加的临床挑战。在慢性疼痛患者中进行的全基因组关联研究已经确定了数百种常见的致病变体，但它们仅解释了慢性疼痛个体差异的一部分。随着下一代测序技术的进步，现在可以在大型数据库中进行更罕见变体的研究。在这里，我们对英国生物库全外显子组测序数据库中的 20 万名人类受试者进行了基于基因的罕见变异分析，以研究 9 种不同的慢性疼痛状态，并在 3 个其他大型数据库中验证了我们的发现。我们的分析在全基因组水平上确定了编码钠/硫酸盐转运体的 SLC13A1 基因与慢性背痛和多部位疼痛有关，在名义水平上与慢性头痛、膝盖、颈部和肩部疼痛有关。在基因座内鉴定出 7 种可能导致慢性疼痛发展的功能丧失性罕见变体，其中 2 种与背痛和多部位疼痛单独相关。然后在另外 3 个生物库中测试了这 2 个罕见变体的复制，发现 rs28364172 作为个体贡献者的最强证据。在神经病理性疼痛测定中，对啮齿动物 Slc13a1 的转录分析表明其在背根神经节和坐骨神经中的表达有很大的调节作用。我们的研究结果强调了 SLC13A1 基因在神经系统硫酸盐稳态中的重要性及其在预防疼痛状态中的关键作用，从而为以个性化方式治疗慢性疼痛，特别是在 SLC13A1 基因突变的人群中，提供了新的治疗方法。
