Blood RNA and protein biomarkers are associated with vaping and dual use, and prospective health outcomes

Background Electronic nicotine delivery systems (ENDS) are driving an epidemic of vaping. Identifying biomarkers of vaping and dual use (concurrent vaping and smoking) will facilitate studies of the health effects of vaping. To identify putative biomarkers of vaping and dual use, we performed association analysis in an observational cohort of 3,892 COPDGene study participants with blood transcriptomics and/or plasma proteomics data and self-reported current vaping and smoking behavior. Methods Biomarkers of vaping and dual use were identified through differential expression analysis and related to prospective health events over six years of follow-up. To assess the predictive accuracy of multi-biomarker panels, we constructed predictive models for vaping and smoking categories and prospective health outcomes. Results We identified three transcriptomic and three proteomic associations with vaping, and 90 transcriptomic and 100 proteomic associations to dual use. Many of these vaping or dual use biomarkers were significantly associated with prospective health outcomes, such as FEV1 decline (three transcripts and 62 proteins), overall mortality (18 transcripts and 73 proteins), respiratory mortality (two transcripts and 23 proteins), respiratory exacerbations (13 proteins) and incident cardiovascular disease (24 proteins). Multimarker models showed good performance discriminating between vaping and smoking behavior and produced informative, modestly powerful predictions of future FEV1 decline, mortality, and respiratory exacerbations. Conclusions In summary, vaping and dual use are associated with RNA and protein blood-based biomarkers that are also associated with adverse health outcomes. ### Competing Interest Statement Competing Interests: EKS and PJC have received grant support from GlaxoSmithKline and Bayer. JY has received institutional grant support from Bayer and personal fees from Bride Biotherapeutics outside the submitted work. ### Funding Statement Funding Sources: This work was supported by NHLBI K08HL141601, K08HL146972, K01HL157613, R01HL124233, U01 HL089897, R01 HL147326, and U01 HL089856. The COPDGene study ([NCT00608764][1]) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. ### 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: Clinical CenterInstitution TitleProtocol Number National Jewish HealthNational Jewish IRBHS1883a Brigham and Womens HospitalPartners Human Research Committee2007P000554 BWH Baylor College of MedicineInstitutional Review Board for Baylor College of Medicine and Affiliated HospitalsH22209 Michael E. DeBakey VAMCInstitutional Review Board for Baylor College of Medicine and Affiliated HospitalsH22202 Columbia University Medical CenterColumbia University Medical Center IRBIRB AAAC9324 Duke University Medical CenterThe Duke University Health System Institutional Review Board for Clinical Investigations (DUHS IRB)Pro00004464 Johns Hopkins UniversityJohns Hopkins Medicine Institutional Review Boards (JHM IRB)NA00011524 Los Angeles Biomedical Research InstituteThe John F. Wolf MD Human Subjects Committee of Harbor UCLA Medical Center1275601 Morehouse School of MedicineMorehouse School of Medicine Institutional Review Board071029 Temple UniversityTemple University Office for Human Subjects Protections Institutional Review Board11369 University of Alabama at BirminghamThe University of Alabama at Birmingham Institutional Review Board for Human UseFO70712014 University of California San DiegoUniversity of California San Diego Human Research Protections Program070876 University of IowaThe University of Iowa Human Subjects Office200710717 Ann Arbor VAVA Ann Arbor Healthcare System IRBPCC 2008110732 University of MinnesotaUniversity of Minnesota Research Subjects Protection Programs (RSPP)0801M24949 University of PittsburghUniversity of Pittsburgh Institutional Review BoardPRO07120059 University of Texas Health Sciences Center at San AntonioUT Health Science Center San Antonio Institutional Review BoardHSC20070644H Health Partners Research FoundationHealth Partners Research Foundation Institutional Review Board07127 University of MichiganMedical School Institutional Review Board (IRBMED)HUM00014973 Minneapolis VA Medical CenterMinneapolis VAMC IRB4128A Fallon ClinicIRB/Research Review Committee St. Vincent Hospital Fallon Clinic Fallon Community Health Plan1143 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online at dbGaP [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00608764&atom=%2Fmedrxiv%2Fearly%2F2022%2F12%2F05%2F2022.09.19.22280093.atom