Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain
Parisien, Marc; van Reij, Roel R.I.; Khoury, Samar; Koseli, Eda; Karaky, Mohamad; Silva, Jaqueline R.; Taheri, Golnar; van den Hoogen, Nynke J.; Peng, Garrie; Allegri, Massimo; De Gregori, Manuela; Chelly, Jacques E.; Rakel, Barbara A.; Aasvang, Eske K.; Kehlet, Henrik; Buhre, Wolfgang F.F.A.; Bryant, Camron D.; Damaj, M. Imad; King, Irah L.; Ghasemlou, Nader; Mogil, Jeffrey S.; Joosten, Elbert A.J.; Diatchenko, Luda
(2024) British Journal of Anaesthesia, volume 133, issue 2, pp. 360 - 370
(Article)
Abstract
Background: 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. Methods: 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.
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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. Results: 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. Conclusions: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.
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Keywords: B cells, chronic post-surgical pain, genome-wide association study, immune system, lymphocytes, Anesthesiology and Pain Medicine
ISSN: 0007-0912
Publisher: Oxford University Press
Note: Publisher Copyright: © 2024 The Authors
(Peer reviewed)