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

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 2 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 postinjury (n = 15/recovery group). Findings were replicated through meta-analyses 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 sex-specific 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 with minimal symptoms. SLC12A1 and MXRA7 showed lower expression in males with moderate/severe pain, whereas HLA-G was upregulated. Gene expression meta-analysis in females identified 6 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 postinjury. Future research is needed to further characterise sex-specific mechanisms after whiplash injury to improve prognosis and targeted management strategies.