Faculty of Dental Medicine and Oral Health Sciences, Department of Anesthesia, Faculty of Medicine, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
Department of Anesthesiology and Pain Management, Maastricht University Medical Center+, School for Mental Health and Neuroscience (MHeNs), Faculty of Health, Medicine and Life Sciences, University of Maastricht, Maastricht, The Netherlands.
Br J Anaesth. 2024 Aug;133(2):360-370. doi: 10.1016/j.bja.2024.04.053. Epub 2024 Jun 10.
Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood.
A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types.
We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia.
These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.
慢性术后疼痛（CPSP）显著影响患者的康复和生活质量。尽管环境风险因素已得到充分证实，但遗传风险仍知之甚少。
对五种手术类型（子宫切除术、乳房切除术、腹部、疝气和膝关节）的 1350 个人进行了全基因组关联研究的荟萃分析，然后进行了分区遗传力分析。在随后的动物研究中，在足底切口和剖腹手术后，测量 Rag1 缺失突变体和野生型小鼠对诱发机械刺激的退缩阈值。通过流式细胞术进行细胞分选，跟踪免疫细胞类型的募集。
我们发现了 77 个全基因组显著的单核苷酸多态性（SNP），分布在 24 个基因座和 244 个基因中。所有队列的荟萃分析估计 CPSP 的 SNP 基于狭义遗传率约为 39%，表明遗传因素有很大贡献。对广泛的组织进行分区遗传力分析显示，免疫系统相关基因的遗传力富集，特别是与 B 和 T 细胞相关的基因。缺乏 T 和 B 细胞的 Rag1 缺失突变体小鼠在手术后长达 42 天表现出加剧和持久的痛觉过敏，通过 B 细胞转移可得到挽救。在足部、淋巴结和背根神经节中，损伤后第 1 天至第 7 天，B 细胞的募集模式而非 T 细胞的募集模式有显著差异。
这些发现表明适应性免疫系统在慢性术后疼痛的发展中起着关键的保护作用。
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