Sex-specific molecular signatures in persistent pain after whiplash injury: an exploratory analysis

Journal article

Introduction:
Whiplash-associated disorder grade II (WADII) is characterised by persistent pain in the absence of frank nerve injury, yet its molecular mechanisms remain unclear.
Objectives:
To identify molecular signatures of two recovery groups characterised by persistent moderate/severe and minimal symptoms in WADII using RNA-sequencing of blood samples 6 months postinjury.
Methods:
We performed bulk transcriptional analyses on blood samples collected from the primary cohort of individuals with WADII 6 months post-injury (n=15/recovery group). Findings were replicated through metaanalyses using an independent cohort of chronic WAD. Blood cellular composition was estimated via deconvolution analyses across both cohorts.
Results:
Although there were no differentially expressed genes between recovery groups, we identified sexspecific gene expression signatures of recovery. In the primary WADII cohort, HLA-DQA1, HEBP1, and NECTIN2 showed lower expression in females with moderate/severe symptoms compared to minimal symptoms. SLC12A1 and MXRA7 showed lower expression in males with moderate/severe pain, while HLA-G was upregulated. Gene expression meta-analysis in females identified six differentially expressed genes, including replication of lower HLA-DQA1 expression from the primary cohort. There were no differentially expressed genes in the meta-analyses in males or between recovery groups. Deconvolution analyses revealed diverging trends between sexes for blood cell types and whiplash symptom severity scores. Ligand-receptor pair analyses further suggested distinct sex-specific recovery trajectories.
Conclusion:
Transcriptional profiling revealed sex-specific molecular blood signatures associated with persistent whiplash symptoms 6 months post-injury. Future research is needed to further characterise sexspecific mechanisms post-whiplash injury to improve prognosis and targeted management strategies.

Authors: Fundaun, J; Ridehalgh, C; Dilley, A; Schmid, AB; Baskozos, G

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Lippincott, Williams & Wilkins
• Journal: PAIN Reports
• Acceptance date: 2026-05-30
• EISSN: 2471-2531
• Language: English
• Keywords: whiplash-associated disorders; RNA-sequencing; chronic pain; neuropathic pain; transcriptional profiling