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 Koseli; Mohamad Karaky; Jaqueline R Silva; Golnar Taheri; Nynke J van den Hoogen; Garrie Peng; Massimo Allegri; Manuela De Gregori; Jacques E Chelly; Barbara A Rakel; Eske K Aasvang; Henrik Kehlet; Wolfgang F F A Buhre; Camron D Bryant; M Imad Damaj; Irah L King; Nader Ghasemlou; Jeffrey S Mogil; Elbert A J Joosten; Luda Diatchenko

doi:10.1016/j.bja.2024.04.053

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 Koseli, Mohamad Karaky, Jaqueline R Silva, Golnar Taheri, Nynke J van den Hoogen, Garrie Peng, Massimo Allegri, Manuela De Gregori, Jacques E Chelly, Barbara A Rakel, Eske K Aasvang, Henrik Kehlet, Wolfgang F F A Buhre, Camron D Bryant, M Imad Damaj, Irah L King, Nader GhasemlouJeffrey S Mogil, Elbert A J Joosten, Luda Diatchenko^*

^*Corresponding author af dette arbejde

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.

Originalsprog	Engelsk
Tidsskrift	British Journal of Anaesthesia
Vol/bind	133
Udgave nummer	2
Sider (fra-til)	360-370
Antal sider	11
ISSN	0007-0912
DOI	https://doi.org/10.1016/j.bja.2024.04.053
Status	Udgivet - 2024

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10.1016/j.bja.2024.04.053

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Parisien, M., van Reij, R. R. I., Khoury, S., Koseli, E., Karaky, M., Silva, J. R., Taheri, G., van den Hoogen, N. J., Peng, G., Allegri, M., De Gregori, M., Chelly, J. E., Rakel, B. A., Aasvang, E. K., Kehlet, H., Buhre, W. F. F. A., Bryant, C. D., Damaj, M. I., King, I. L., ... Diatchenko, L. (2024). Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain. British Journal of Anaesthesia, 133(2), 360-370. https://doi.org/10.1016/j.bja.2024.04.053

Parisien, M, van Reij, RRI, Khoury, S, Koseli, E, Karaky, M, Silva, JR, Taheri, G, van den Hoogen, NJ, Peng, G, Allegri, M, De Gregori, M, Chelly, JE, Rakel, BA, Aasvang, EK , Kehlet, H, Buhre, WFFA, Bryant, CD, Damaj, MI, King, IL, Ghasemlou, N, Mogil, JS, Joosten, EAJ & Diatchenko, L 2024, 'Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain', British Journal of Anaesthesia, bind 133, nr. 2, s. 360-370. https://doi.org/10.1016/j.bja.2024.04.053

@article{77023e20fd4341b288f445f5575fa549,

title = "Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain",

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.",

keywords = "Animals, B-Lymphocytes/immunology, Chronic Pain/genetics, Disease Models, Animal, Female, Genome-Wide Association Study, Humans, Hyperalgesia/genetics, Male, Mice, Mice, Knockout, Pain, Postoperative/genetics, Polymorphism, Single Nucleotide, lymphocytes, B cells, chronic post-surgical pain, genome-wide association study, immune system",

author = "Marc Parisien and {van Reij}, {Roel R I} and Samar Khoury and Eda Koseli and Mohamad Karaky and Silva, {Jaqueline R} and Golnar Taheri and {van den Hoogen}, {Nynke J} and Garrie Peng and Massimo Allegri and {De Gregori}, Manuela and Chelly, {Jacques E} and Rakel, {Barbara A} and Aasvang, {Eske K} and Henrik Kehlet and Buhre, {Wolfgang F F A} and Bryant, {Camron D} and Damaj, {M Imad} and King, {Irah L} and Nader Ghasemlou and Mogil, {Jeffrey S} and Joosten, {Elbert A J} and Luda Diatchenko",

year = "2024",

doi = "10.1016/j.bja.2024.04.053",

language = "English",

volume = "133",

pages = "360--370",

journal = "British Journal of Anaesthesia",

issn = "0007-0912",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

T1 - Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain

AU - Parisien, Marc

AU - van Reij, Roel R I

AU - Khoury, Samar

AU - Koseli, Eda

AU - Karaky, Mohamad

AU - Silva, Jaqueline R

AU - Taheri, Golnar

AU - van den Hoogen, Nynke J

AU - Peng, Garrie

AU - Allegri, Massimo

AU - De Gregori, Manuela

AU - Chelly, Jacques E

AU - Rakel, Barbara A

AU - Aasvang, Eske K

AU - Kehlet, Henrik

AU - Buhre, Wolfgang F F A

AU - Bryant, Camron D

AU - Damaj, M Imad

AU - King, Irah L

AU - Ghasemlou, Nader

AU - Mogil, Jeffrey S

AU - Joosten, Elbert A J

AU - Diatchenko, Luda

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - Animals

KW - B-Lymphocytes/immunology

KW - Chronic Pain/genetics

KW - Disease Models, Animal

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Hyperalgesia/genetics

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Pain, Postoperative/genetics

KW - Polymorphism, Single Nucleotide

KW - lymphocytes

KW - B cells

KW - chronic post-surgical pain

KW - genome-wide association study

KW - immune system

UR - http://www.scopus.com/inward/record.url?scp=85195490360&partnerID=8YFLogxK

U2 - 10.1016/j.bja.2024.04.053

DO - 10.1016/j.bja.2024.04.053

M3 - Journal article

C2 - 38862382

SN - 0007-0912

VL - 133

SP - 360

EP - 370

JO - British Journal of Anaesthesia

JF - British Journal of Anaesthesia

IS - 2

ER -

Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain

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