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

Whiplash-associated disorder grade II (WADII) is characterised by persistent pain in the absence of frank nerve injury, yet its molecular mechanisms remain unclear.

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.

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.

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.

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.