Large‐Scale Plasma Proteomics to Profile Pathways and Prognosis of Chronic Pain

Abstract While increasing peripheral mechanisms related to chronic pain, the plasma proteomics profile associated with it and its prognosis remains elusive. This study utilizes 2923 plasma proteins and chronic pain of 51 644 participants from UK Biobank and finds 474 proteins linked to chronic pain in six sites: head, neck or shoulder, back, stomach or abdominal, hip, and knee, with 11 proteins sharing across pain sites. The identified proteins are largely enriched in immune and metabolic pathways and highly expressed in tissues like lungs and small intestines. Phenome‐wide analysis highlights the significance of pain‐related proteome on diverse facets of human health, and in‐depth Mendelian randomization validates 10 proteins (CD302, RARRES2, TNFRSF1B, BTN2A1, TNFRSF9, COL18A1, TNF, CD74, TNFRSF4, and BTN2A1) as markers of chronic pain. Furthermore, protein sets capable of classifying pain patients and healthy participants, particularly performing best in hip pain (area under curve, AUC = 0.725), are identified. Interestingly, the prediction of pain spreading over ten years achieves an AUC of 0.715, with leptin identified as a crucial predictor. This study delineates proteins associated with various pain conditions and identifies proteins capable of classifying pain and predicting pain spreading, offering benefits for both research and clinical practice.