Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank

Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank | medRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank View ORCID Profile Steven Lehrer , Peter Rheinstein doi: https://doi.org/10.64898/2026.03.17.26348624 Steven Lehrer 1 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai New York MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Steven Lehrer For correspondence: stevenlehrer{at}hotmail.com Peter Rheinstein 2 Severn Health Solutions Severna Park , Maryland MD, JD, MS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Background The transition from acute to chronic pain represents a failure of physiological resolution. While systemic immune cell counts and androgen levels have been associated with this transition, the specific molecular mediators remain poorly understood. We sought to identify the functional proteomic drivers of long-term pain persistence and determine their independence from systemic factors. Methods We identified a longitudinal persistence cohort (N=3,221) within the UK Biobank who reported acute pain at baseline and were followed for resolution or persistence. Using the Olink Explore 3072 platform, we screened 2,923 serum proteins. Multivariable competition models were employed to evaluate the independent predictive power of top proteomic hits alongside systemic monocyte counts and circulating free testosterone levels, adjusted for age and sex. Results Our proteome-wide screen identified Lactoperoxidase (LPO) as a dominant and highly significant predictor of pain persistence. In the fully adjusted competition model, each standard deviation increase in LPO was associated with a 59% increase in the odds of persistence (OR 1.59, 95% CI 1.25–2.07, p < 0.001) . Notably, after accounting for LPO, systemic monocyte counts ( OR 0.93, p = 0.55 ) and testosterone levels ( OR 0.82, p = 0.46 ) were no longer significant predictors. Nogo Receptor (RTN4R) also remained a significant predictor in independent models (OR 1.44, p = 0.002). Conclusions These exploratory findings demonstrate that long-term pain persistence is associated with specific functional molecular signatures rather than broad systemic cell quantity. The dominance of LPO suggests that secretory peroxidase-driven pathways may be a primary barrier to pain resolution. Furthermore, the association of RTN4R identifies neural repair inhibition as a candidate driver of persistence. These proteins are candidates for further mechanistic investigation. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was conducted using the UK Biobank Resource under Application Number 57245. UK Biobank has ethical approval from the North West Multi-centre Research Ethics Committee (MREC) (reference 11/NW/0382), and all participants provided written informed consent for data collection, analysis, and record linkage. The present study was conducted in accordance with the principles of the Declaration of Helsinki. All analyses were performed using de-identified data provided by UK Biobank, and no additional ethical approval was required for this secondary analysis. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The data analyzed in this study were obtained from the UK Biobank (UKBB) Resource under Application Number 57245. The raw datasets, including the UKB Pharma Proteomics Project (UKB-PPP) Olink data, hematology, and touchscreen questionnaires, are available to bona fide researchers upon application to the UK Biobank ( www.ukbiobank.ac.uk/enable-your-research/apply-for-access ). Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted March 19, 2026. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank Steven Lehrer , Peter Rheinstein medRxiv 2026.03.17.26348624; doi: https://doi.org/10.64898/2026.03.17.26348624 Share This Article: Copy Citation Tools Identification of LPO and RTN4R as Proteomic Signatures of Pain Persistence: An Exploratory Analysis of the UK Biobank Steven Lehrer , Peter Rheinstein medRxiv 2026.03.17.26348624; doi: https://doi.org/10.64898/2026.03.17.26348624 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Pain Medicine Subject Areas All Articles Addiction Medicine (638) Allergy and Immunology (917) Anesthesia (350) Cardiovascular Medicine (4998) Dentistry and Oral Medicine (494) Dermatology (427) Emergency Medicine (676) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1690) Epidemiology (16252) Forensic Medicine (36) Gastroenterology (1241) Genetic and Genomic Medicine (7274) Geriatric Medicine (751) Health Economics (1093) Health Informatics (5283) Health Policy (1467) Health Systems and Quality Improvement (1832) Hematology (599) HIV/AIDS (1380) Infectious Diseases (except HIV/AIDS) (16483) Intensive Care and Critical Care Medicine (1203) Medical Education (699) Medical Ethics (156) Nephrology (751) Neurology (7585) Nursing (377) Nutrition (1127) Obstetrics and Gynecology (1295) Occupational and Environmental Health (1039) Oncology (3742) Ophthalmology (1092) Orthopedics (407) Otolaryngology (465) Pain Medicine (501) Palliative Medicine (143) Pathology (721) Pediatrics (1858) Pharmacology and Therapeutics (755) Primary Care Research (786) Psychiatry and Clinical Psychology (6122) Public and Global Health (9984) Radiology and Imaging (2528) Rehabilitation Medicine and Physical Therapy (1516) Respiratory Medicine (1268) Rheumatology (658) Sexual and Reproductive Health (804) Sports Medicine (595) Surgery (802) Toxicology (109) Transplantation (318) Urology (307)

Related documents

• Structural phenotypes of osteoarthritis are clinically and genetically distinct: findings from 59,539 UK Biobank participants#395198
• Existential Genomics: Effects of Multimodal Rehabilitation and Integrative Care on Patients With Chronic Pain#871134
• UK Medical Cannabis Registry: An Updated Analysis of Inflammatory Arthritis.#685730
• Pharmacogenomics Applied to Chronic Pain Treatment in Primary Care#980448
• Integrated analysis of single-cell and transcriptome data reveals temporal dynamics of microglial phagocytic reprogramming in neuropathic pain progression#784524