Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain
Marc Parisien, Roel R.I. van Reij, Samar Khoury, Eda Köşeli, Mohamad Karaky, Jaqueline Raymondi Silva, Golnar Taheri, Nynke J. van den Hoogen, Garrie Peng, Massimo Allegri, Manuela De Gregori, Jacques E. Chelly, Barbara A. Rakel, Eske Kvanner Aasvang, Henrik Kehlet, Wolfgang Bühre, Camron D. Bryant, M. Imad Damaj, Irah L. King, Nader Ghasemlou, Jeffrey S. Mogil, Elbert A.J. Joosten, Luda Diatchenko
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. 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.